Pyrazole derivatives useful as 5-lipoxygenase activating protein (flap) inhibitors

ABSTRACT

The present application relates to novel compounds of formula (I) to their utility in treating and/or preventing clinical conditions including cardiovascular diseases (CVD), to methods for their therapeutic use, to pharmaceutical compositions containing them and to processes for preparing such compounds.

FIELD

The present application relates to novel compounds that inhibit5-lipoxygenase activating protein (FLAP) and therefore leukotrieneproduction, to their utility in treating and/or preventing clinicalconditions including cardiovascular diseases (CVD), such asatherosclerosis, coronary artery disease (CAD), coronary heart disease(CHD), heart failure (HF), high risk coronary artery disease (HRCAD),and abdominal aortic aneurysms (AAA), to methods for their therapeuticuse, to pharmaceutical compositions containing to them and to processesfor preparing such compounds.

BACKGROUND

FLAP, 5-lipoxygenase activating protein, plays a critical role in theproduction of leukotrienes by the 5-lipoxygenase (5-LO) pathway. Inparticular, FLAP mediates the transfer of the substrate, arachidonicacid, released from membrane phospholipids to the active site of 5-LO.Leukotrienes are lipid mediators released by leukocytes, in particularneutrophils, eosinophils, mast cells and monocyte/macrophages. Theybelong to the wider class of lipid mediators known as eicosanoids,formed from arachidonic acid released from cell membranes. Two distinctclasses of leukotriene exist, LTB₄ and CysLTs (LTC₄, LTD₄ and LTE₄).Functions of LTB₄ include chemo-attraction and activation of leukocytes,inhibition of neutrophil apoptosis, and activation of adhesion moleculeexpression. Such effects are mediated through binding to one of twodistinct G protein-coupled receptors (BLT1 and BLT2) which differ intheir affinity and specificity for LTB₄. Cysteinyl leukotrienes havevaso-active properties and can affect blood flow and vasopermeability,actions that are mediated by two CysLT receptors, CysLT1 and CysLT2.

To initiate leukotriene biosynthesis, 5-LO translocates to intracellularmembranes such as the nuclear membrane where it interacts with FLAP.Arachidonic acid released from membrane phospholipids by cytoplasmicPLA2 (cPLA₂) is transferred via FLAP to 5-LO which thenstereospecifically incorporates oxygen at the fifth carbon position,with the formation of 5(S)-HpETE. This is subsequently converted by 5-LOto LTA₄, the common precursor for leukotriene B₄ (LTB₄) and thecysteinyl leukotrienes (LTC₄, LTD₄ and LTE₄). The conversion of LTA₄ toLTB₄ is mediated by LTA₄ Hydrolase (LTA₄H), a zinc-dependent epoxidehydrolase. Formation of cysteinyl leukotrienes involves conjugation ofLTA₄ to glutathione, mediated by LTC₄ synthase in cell membranes inassociation with FLAP, and the resulting LTC₄ may be further processedto LTD₄ and LTE₄ via peptidase activities.

Compounds that inhibit the function of either 5-LO or FLAP can result inthe inhibition of leukotriene production. FLAP inhibitors bind directlyto FLAP in cell membranes and prevent leukotriene biosynthesis bypreventing the membrane translocation of 5-LO and/or the supply ofarachidonic acid substrate to its active site. In this way, inhibitionof FLAP prevents the production of both LTB₄ and cysLTs by inhibitingproduction of the common precursor LTA₄. Distinct from 5-LO inhibitors,FLAP inhibitors do not directly suppress oxidation of arachidonic acidby 5-LO and do not inhibit leukotriene production in lysed cellextracts.

Despite the availability of drugs that deal with risk factors such ashigh cholesterol levels and elevated blood pressure, further treatmentoptions are needed to reduce atherosclerotic cardiovascular disease andits sequellae. The role of lipid deposition in the formation ofatherosclerotic plaques is well-established. However, another key factorin atherogenesis is inflammation, including both the recruitment ofinflammatory cells to atherosclerotic lesions and their activationwithin plaques. Pharmacological approaches that target inflammationcould therefore provide a novel approach to treating patients withatherosclerosis. Inhibition of leukotriene production by means ofadministering a FLAP inhibitor is one such approach.

Another risk factor associated with cardiovascular disease ismicrovascular dysfunction. By attenuating leukocyte activation andinteraction with the microvasculature in addition to reducing theproduction of vasoactive cysteinyl leukotrienes, pharmacologicalinhibition of FLAP could improve microvascular function incardiovascular disease patients.

A link between FLAP, 5-LO pathway activity, leukotriene production andcardiovascular disease is supported by the following lines ofevidence: 1) expression and activity of the 5-LO pathway increases inassociation with atherosclerotic plaque progression and symptoms ofplaque instability that could cause plaque rupture and thrombosisleading to myocardial infarction (MI) (Spanbroek et al (2003) PNAS 100,1238; Cipollone et al (2005) ATVB 25, 1665); 2) leukotriene levels inblood and urine are elevated in the period following a recent acutecoronary syndrome (ACS) event (Sanchez-Gala et al (2009) CardiovascularResearch 81, 216; Carry et al (1992) Circulation 85, 230); 3) genetichaplotypes in the FLAP (ALOX5AP) gene are significantly associated withthe risk of myocardial infarction (Helgadottir et al (2004) NatureGenetics 36, 233).

Many companies over the course of the last few decades have pursued FLAPas a target, and patent filings associated with these efforts aresummarized in various publications. See e.g., Pergola & Werz, ExpertOpin. Ther. Patents (2010) 20(3); and Hofmann & Steinhilber Expert Opin.Ther. Patents, (2013) 23(7) and Whatling Bioorg. Med Chem. Lett. (2015)25(2607). However, this application presents a new class of compoundsdistinct from these prior patent filings.

The instant application addresses the large unmet need by providingcompounds, compositions and methods for the treatment or prevention ofcardiovascular disease and related conditions.

BRIEF DESCRIPTION

In one aspect, there is provided a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein, R¹ is H, C₁-C₃alkyl, halo, C₁-C₃ alkoxy, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy; each ofR² and R³ is independently H, C₁-C₃ alkyl, C₁-C₃ alkoxy, —CN or halo; R⁴is H, —CH₃, —CH₂F, —CHF₂, —CF₃ or halo; Ring A contains 2 double bonds;each X₁, X₂, X₃ and X₄ of Ring A is independently CR⁵, CH, O, S, NR⁶ orN; wherein at least one of X₁, X₂, X₃ and X₄ in Ring A is NR⁶; each R⁵is optionally and independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃ haloalkoxy, —S(O)_(p)R⁷, —CN, —CONR′R″, or C₃-C₆cycloalkyl; each p is independently 0, 1 or 2; or wherein when X₄ is CR⁵and X₃ is NR⁶, then the R⁵ and R⁶ may be taken together to form a 5 to6-membered heterocyclyl ring fused to Ring A, which heterocyclyl mayoptionally contain an additional heteroatom selected from N, O and S;said fused heterocyclyl may additionally contain a carbonyl or a —S(O)₂directly adjacent to a heteroatom therein; and may be furthersubstituted with one or two substituents selected from the groupconsisting of —CH₃ and halo; R⁶ is H, —CH₃ or —CH₂CH₃; R⁷ is —CH₃ or—NR′R″; and each R′ and R″ is independently —H or —CH₃; provided thatthe total number of substituents on Ring A is 0, 1 or 2; and furtherprovided that when R⁵ and R⁶ are not combined to form a heterocyclylring fused to Ring A, that the total number of R⁵ and R⁶ substituentswhich is alkyl and/or haloalkyl is 0 or 1.

In a further aspect, there is provided pharmaceutical compositionscomprising a therapeutically effective amount of the compound of formula(I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable diluent, excipients and/or inert carrier.

In still a further aspect, there is provided the compound of formula (I)or a pharmaceutically acceptable salt thereof, for use in treatment orprophylaxis of diseases and conditions in which inhibition of FLAP isbeneficial. In one embodiment, is a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofcardiovascular disease. In one embodiment, the cardiovascular disease iscoronary artery disease, particularly high risk coronary artery disease.

In one aspect there is provided a method of treating diseases orconditions in which inhibition of FLAP is beneficial, comprisingadministering to a patient in need thereof an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.In one embodiment, said disease or condition is coronary artery disease.In another embodiment, said disease or condition is high risk coronaryartery disease.

In one aspect, is a compound according to formula (I), or apharmaceutically acceptable salt thereof, for use as medicament.

In another aspect there is provided a process for the preparation ofcompounds of formula (I), and the intermediates used in the preparationthereof.

These and other aspects of the present application are described ingreater detail herein below.

DETAILED DESCRIPTION

The object of the present application is to provide compounds that areinhibitors of 5-lipoxygenase activating protein (FLAP), their use asmedicaments, pharmaceutical compositions containing them and syntheticroutes to their production.

In one embodiment is a compound according to formula (I), or apharmaceutically acceptable salt thereof, as described above.

In another embodiment is a compound according to formula (II):

or a pharmaceutically acceptable salt thereof, wherein each X₁, X₂ andX₄ of Ring A is to independently CR⁵, CH, or N; wherein at least one ofX₁, X₂ and X₄ in Ring A is N; and X₃ is O, S or NR⁶; or wherein when X₄is CR⁵ and X₃ is NR⁶, then the R⁵ and R⁶ may be taken together to form a5 to 6-membered heterocyclyl ring fused to Ring A, which heterocyclylmay optionally contain an additional heteroatom selected from N, O andS; said fused heterocyclyl may additionally contain a carbonyl or a—S(O)₂ directly adjacent to a heteroatom therein; and may be furthersubstituted with one or two substituents selected from the groupconsisting of —CH₃ and halo; R¹, R², R⁴, R⁵ and R⁶ are as hereinabovedefined.

A further embodiment is a compound according to formula (III):

or a pharmaceutically acceptable salt thereof; wherein X¹ is CH or CR⁵;X² is N; X³ is O, S, or NR⁶; X⁴ is CH or CR⁵; R² is —H or F; R⁵ is—S(O)₂NR′R″, —SO₂CH₃; —C(O)NR′R″, —CN, C₁-C₂ alkoxy, C₁-C₂ haloalkoxy orC₁-C₂ haloalkyl; R⁶ is H, —CH₃ or —CH₂CH₃; and each R′ and R″ isindependently —H or —CH₃; or wherein when X₄ is CR⁵ and X₃ is NR⁶, thenthe R⁵ and R⁶ may be taken together to form a 5 to 6-memberedheterocyclyl ring fused to Ring A, which heterocyclyl may optionallycontain an additional heteroatom selected from N, O and S; said fusedheterocyclyl may additionally contain a carbonyl or a —S(O)₂ directlyadjacent to a heteroatom therein; and may be further substituted withone or two substituents selected from the group consisting of —CH₃ andhalo; and R⁴ is as hereinabove defined.

A further embodiment is a compound according to formula (III) or apharmaceutically acceptable salt thereof; wherein X¹ is CH or CR⁵; X² isN; X³ is O, S, or NR⁶; X⁴ is CH or CR⁵; R² is —H or F; R⁵ is—S(O)₂NR′R″, —SO₂CH₃; —C(O)NR′R″, —CN, C₁-C₂ alkoxy, C₁-C₂ haloalkoxy orC₁-C₂ haloalkyl; R⁶ is H, —CH₃ or —CH₂CH₃; and each R′ and R″ isindependently —H or —CH₃; and R⁴ is as hereinabove defined.

The compound according to formula (III), as defined hereinabove whereinone of X¹ is CH, X² is N and X³ is NR⁶; and R⁶ is as hereinabovedefined.

A further embodiment is a compound according to formula (III), asdefined hereinabove, wherein R⁵ is —S(O)₂CH₃, —CHF₂ or —OCHF₂.

A further embodiment is a compound according to formula (III), asdefined hereinabove, wherein R⁵ is —S(O)₂NH₂, —C(O)NH₂ or —CN; and R⁶ is—H or —CH₃.

The compound according to formula (III), as defined hereinabove whereinone of X¹ is CH, X² is N and X³ is NR⁶; and R⁶ is as hereinabovedefined.

One embodiment is a compound according to formula (IV):

or a pharmaceutically acceptable salt thereof, wherein X¹ is CH or CR⁵;R⁵, if present, is —CH₃; R² is —H or —F; R⁴ is —H or —CH₃; and R⁸ is —Hor CH₃.

Another embodiment is a compound according to formula (V):

or a pharmaceutically acceptable salt thereof, wherein X¹ is CH or CR⁵;R² is —H or —F; R⁴ is —H or —CH₃; R⁵, if present, is —CH₃; and R⁶ is —Hor —CH₃; provided that R⁵ and R⁶ are not both —CH₃ at the same time.

A further embodiment is a compound according to formula (VI):

or a pharmaceutically acceptable salt, wherein X¹ is CH or CR⁵; R² is —Hor —F; R⁴ is —H or —CH₃; R⁵, if present, is —CH₃; and R⁶ is —H or —CH₃;R⁷ is —CH₃ or —NR′R″; and each R′ and R″ is independently —H or —CH₃;provided that R⁵ and R⁶ are not both —CH₃ at the same time.

Another embodiment is a compound according to formula (VII):

or a pharmaceutically acceptable salt, wherein one of X¹ and X⁴ is CH,and the other is CR⁵; R² is —H or —F; R⁴ is —H or —CH₃; R⁵ is —CH₃ orC₁-haloalkyl; and R⁶ is —H or —CH₃, provided that the total number of R⁵and R⁶ substituents in the A ring which is alkyl is 0 or 1.

In one aspect, for any one of formulae (I), (II), (III), (IV), (V), (VI)or (VII), or a pharmaceutically acceptable salt thereof, R¹ is —H.

In one aspect, for a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, R² and R³ are each independently —F or —H. Inanother aspect for any of formulae (I), (II), (III), (IV), (V), (VI) or(VII), or a pharmaceutically acceptable salt thereof, R² is —H or —F andR³ is —H. In a further aspect, for any of formulae (I), (II), (III),(IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof,R² is —H and R³ is —H.

In one aspect, for any one of formulae (I), (II), (III), (IV), (V), (VI)or (VII), or a pharmaceutically acceptable salt thereof, R⁴ is —H. Inanother aspect for any one of formulae (I), (II), (III), (IV), (V), (VI)or (VII), or a pharmaceutically acceptable salt thereof, R⁴ is —CH₃.

In one aspect, for any one of formulae (I), (II), (III), (IV), (V), (VI)or (VII), or a pharmaceutically acceptable salt thereof, R¹ is —H; R²and R³ are both —H; and R⁴ is —H or —CH₃.

In one aspect for any one of formulae (II), (III) or (VII), or apharmaceutically acceptable salt thereof, X¹ is CH or CR⁵. In anotheraspect of this embodiment, X⁴ is CR⁵.

In one aspect, for any one of formulae (I), (II) or (III), or apharmaceutically acceptable salt thereof, Ring A is optionally andindependently substituted pyrazole, triazole, oxazole, thiazole,oxadiazole or thiadiazole.

In one aspect, for any of formulae (II) or (III), or a pharmaceuticallyacceptable salt thereof, one of X² is N and X³ is NR⁶.

In one aspect, for any of formulae (I), (II), (III), (V) or (VII), or apharmaceutically acceptable salt thereof, R⁵ is —S(O)₂NH₂, —C(O)NH₂ or—CN; and R⁶ is —H or —CH₃. In one aspect, for any of formulae (I), (II),(III), (V) or (VII), or a pharmaceutically acceptable salt thereof, R⁵is —S(O)₂CH₃, —CHF₂ or —OCHF₂.

In one aspect, for any of formulae (I), (II) or (III), or apharmaceutically acceptable salt thereof, X⁴ is CR⁵ and X³ is NR⁶ andtogether the R⁵ and R⁶ substituents form a 5 to 6 membered heterocyclylring fused to Ring A, selected from:

In another aspect X¹ is CH and X² is N in the bicyclic rings formed fromring A and the heterocyclic ring formed by R⁵ and R⁶ above.

In another aspect, for any of formulae (I), (II) or (III), or apharmaceutically acceptable salt thereof, X⁴ is CR⁵ and X³ is NR⁶ andtogether the R⁵ and R⁶ substituents form a 5 to 6 membered heterocyclylring fused to Ring A, selected from:

In another aspect X¹ is CH and X² is N in the bicyclic rings formed fromring A and the heterocyclic ring formed by R⁵ and R⁶ above.

Any embodiment described herein can be combined with any other suitableembodiment described herein to provide additional embodiments. Forexample, where one embodiment individually or collectively describespossible groups for R¹ and a separate embodiment describeds possiblegroups for R², it is understood that these embodiments can be combinedto provide an additional embodiment utilizing the possible groups for R¹with the possible groups for R². Analogously, the applicationencompasses any embodiments called out individually for R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, X¹, X², X³, X⁴, Ring A, R′ and R″ in combination withany specific embodiments called out for each of the remaining variables.

Compounds of the application include the following:

Example No. Structure Name 1

1-Methyl-4-[({(1R,2R or 1S,2S)-2-[4-(1H- pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole- 3-carboxamide (+)-trans or(−)-trans 2

1-Methyl-4-[({(1R,2R)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}carbonyl)amino]- 1H-pyrazole-5-carboxamide 3

1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H- pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]- 1H-pyrazole-5-carboxamide 4

1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H- pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]- 1H-pyrazole-3-carboxamide 5a

(1S,2S or 1R,2R)-N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H- pyrazol-5-yl)benzoyl]cyclohexanecarboxamide (−)-trans 5b

(1R,2R or 1S,2S)-N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H- pyrazol-5-yl)benzoyl]cyclohexanecarboxamide (+)-trans 6

(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5- yl)benzoyl]-N-(1H-pyrazol-4-yl)cyclohexanecarboxamide 7

(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5- yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)cyclohexanecarboxamide 8

((1R,2R)-N-[1-Methyl-5-(methylsulfonyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5- yl)benzoyl]cyclohexanecarboxamide 9

(1R,2R)-N-[3-(Difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide 10

(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-3-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide 11

(1R,2R)-N-(2,3-Dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)-2-[4-(3-methyl-1H- pyrazol-5-yl)benzoyl]cyclohexanecarboxamide 12

(1R,2R or 1S,2S)-N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3- yl)benzoyl]cyclohexanecarboxamide(−)-trans 13

(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide 14

(1R,2R and 1S,2S)-N-(5-Methoxy-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide (±)-trans 15

(1R,2R)-N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide 16

(1R,2R)-N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2- [4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide 17

(1R,2R)-N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2- [4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide 18a

(1R,2R or 1S,2S)-N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3- yl)benzoyl]cyclohexanecarboxamide(−)-trans 18b

(1S,2S or 1R,2R)-N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3- yl)benzoyl]cyclohexanecarboxamide(+)-trans 19

1-Ethyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}- carbonyl)amino]-1H-pyrazole-5-carboxamide 20

N,1-Dimethyl-4-[({(1R,2R and 1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}- carbonyl)amino]-1H-pyrazole-3-carboxamide (±)-trans 21

N,1-Dimethyl-4-[({(1R,2R)-2-[4-(5- methyl-1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole- 5-carboxamide 22

5-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H- pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole- 3-carboxamide 23

4-[({(1R,2R)-2-[4-(1H-Pyrazol-5- yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide 24

(1R,2R)-N-(4-Oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-5- yl)benzoyl]cyclohexanecarboxamide 25

(1R,2R)-N-[1-Methyl-5- (melhyIsulfamoyl)-1H-pyrazol-4-yl]-2-[4-(3-methyl-1H-pyrazol-5- yl)benzoyl]cyclohexanecarboxamide 26

(1R,2R)-N-(1-Methyl-3-sulfamoyl-1H- pyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide 27

(1R,2R)-N-[5-(Dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide 28

(1R,2R)-N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2- [4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide 29

(1R,2R)-N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2- [4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide 30

(1R,2R)-N-[5-(Difluoromethyl)-1H- pyrazol-4-yl]-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide 31

4-[({(1R,2R and 1S,2S)-2-[2-Chloro-4- (1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1-methyl-1H- pyrazole-5-carboxamide (±)-trans32

4-[({(1R,2R and 1S,2S)-2-[2-Chloro-4-(3- methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1-methyl-1H- pyrazole-5-carboxamide (±)-trans33

(1R,2R and 1S,2S)-N-(5-Cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-[4-(1H- pyrazol-5-yl)benzoyl]cyclohexanecarboxamide (±)-trans 34

4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H- pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1-methyl-1H- pyrazole-5-carboxamide (−)-transor (+)-trans 35

4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl} carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide (−)-trans or (+)-trans 36

4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3- methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1-methyl-1H- pyrazole-3-carboxamide (−)-transor (+)-trans 37

4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3- methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1-methyl-1H- pyrazole-5-carboxamide (+)-trans38

4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3- methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole- 5-carboxamide (−)-trans or(+)-trans 39

(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)cyclohexanecarboxamide(−)-trans or (+)-trans 40

4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3- methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1,2,5- oxadiazole-3-carboxamide (−)-trans or(+)-trans 41

3-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H- pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-5-methyl-1,2- oxazole-4-carboxamide (−)-transor (+)-trans 42

1-Ethyl-4-[({(1R,2R and 1S,2S)-2-[4-(1H- pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole- 3-carboxamide (±)-trans 43

(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5- yl)benzoyl]-N-(1,3,4-oxadiazol-2-yl)cyclohexanecarboxamide 44

(1R,2R and 1S,2S)-N-(3-Methyl-1,2- oxazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide (±)-trans 45

(1R,2R and 1S,2S)-N-(4-Methyl-1,3- oxazol-2-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide (±)-trans 46

(1R,2R and 1S,2S)-N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H- pyrazol-5-yl)benzoyl]cyclohexanecarboxamide (±)-trans 47

(1R,2R and 1S,2S)-N-(3-Cyclopropyl-1,2,4-thiadiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide (±)-trans 48

(1R,2R and 1S,2S)-N-(3-Methyl-1,2- thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide (±)-trans 49

(1R,2R and 1S,1S)-N-(4-Cyano-3-methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5- yl)benzoyl]cyclohexanecarboxamide(±)-trans

In one aspect, the compound of formula (I) is selected from the group ofexamples 1-49 shown above, or a pharmaceutically acceptable saltthereof. It shall be noted that any one of these specific compounds maybe disclaimed from any of the herein mentioned embodiments.

Another aspect is a product obtainable by any of the processes orexamples disclosed herein.

Listed below are definitions of various terms used in the specificationand claims to describe some terms used herein.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by “defined above” the said groupencompasses the first occurring and broadest definition as well as eachand all of the other definitions for that group.

For the avoidance of doubt it is to be understood that in thisspecification “C₁-C₆” means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms, “C₁-C₄” means a carbon group having 1, 2, 3 or 4 carbonatoms, “C₁-C₃” means a carbon group having 1, 2 or 3 carbon atoms, and“C₁-C₂” means a carbon group having 1 or 2 carbon atoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups and may be, butis not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl,i-hexyl or t-hexyl.

In this specification, unless stated otherwise, the term “haloalkyl”means an alkyl group containing one or more halogen atoms, and includes,but is not limited to, monofluoromethyl, difluoromethyl,trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl or3,3,3-trifluoroethyl.

In this specification, unless otherwise stated, the term “alkoxy”includes both straight and branched chain alkyl group containing anoxygen atom, which an attachment point of said group being through theoxygen atom. Examples include, but are not limited to, methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, s-butoxy, t-butoxy, and the like.

In this specification, unless otherwise stated, the term “haloalkoxy”means an alkoxy group, as described above, wherein one more of thehydrogen atoms on the alkyl portion is substituted with a halogen atom.Examples of this include, but are not limited to, monofluoromethoxy,difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, 3-monofluoropropoxy, 3,3-difluoropropoxy and3,3,3-trifluoropropoxy.

In this specification, unless stated otherwise, the term “halo” refersto fluoro, chloro or bromo.

In this specification, unless stated otherwise, the term “C₃-C₆cycloalkyl” means a saturated cyclic alkyl group of 3-6 carbon atoms,and includes, but is not limited to, cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

In this specification, unless stated otherwise, the term “5 to 6membered heterocyclyl” refers to a saturated or partially saturated,non-aromatic monocyclic ring containing 5 to 6 ring atoms, of which atleast one ring atom is selected from nitrogen, sulfur, and oxygen, andof which a —CH₂— group may be optionally replaced by a —C(O)— group.Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ringsulfur atoms may be optionally oxidized to form S-oxides or sulphones.Said heterocyclyl ring may optionally be substituted with one or twosubstituents selected from the group consisting of methyl and halo.Examples of a a 5-6 membered heterocyclyl ring includes, but are notlimited to pyrrolidinyl, imidazolidinyl, oxazolidine, 4-oxooxazolidinyl,thiazolidinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, oxazinanyl,2-oxopyrrolidinyl, 1,3-thiazinanyl and oxo-1,3-thiazolidinyl. In thecontext of this application, a 5-6 membered heterocyclyl may be fused toRing A when X³ is NR⁶ and X⁴ is CR⁵ and the R⁵ and R⁶ substituents aretaken together to form the heterocyclyl. The ring systems described inthis paragraph describe only half of the bicyclic ring system, andinclude the nitrogen atom and carbon atom from Ring A, with X¹ and X² asdefined for Formula (I).

For the avoidance of doubt by ‘said fused heterocyclyl may additionallycontain a carbonyl or a —S(O)₂ directly adjacent to a heteroatomtherein’ in the definition of R⁵ and R⁶, it is meant that the ring atomadjacent to a ring heteroatom in the fused heterocycle may be a ringcarbon substituted by an oxo or a ring sulphur atom oxidised to an S(O)₂respectively.

In this specification, unless otherwise state, the term “high riskcoronary artery disease” as used herein refers to recent acute coronarysyndrome (ACS) or by biomarkers of microvascular and cardiac function.Such biomarkers may include inflammatory biomarkers such as leukotrienesand interleukins, leukocyte counts and/or markers for cardiac andvascular function such as CFR, NT-Pro-BNP and/or TnT.

In this specification, unless otherwise stated, the term“pharmaceutically acceptable” as used herein refers to those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

In this specification, unless otherwise stated, the phrase “effectiveamount” means an amount of a compound or composition which is sufficientenough to significantly and positively modify the symptoms and/orconditions to be treated (e.g., provide a positive clinical response).The effective amount of an active ingredient for use in a pharmaceuticalcomposition will vary with the particular condition being treated, theseverity of the condition, the duration of the treatment, the nature ofconcurrent therapy, the particular active ingredient(s) being employed,the particular pharmaceutically-acceptable excipient(s)/carrier(s)utilized, and like factors within the knowledge and expertise of theattending physician.

Compounds of Formulae (I), (II), (III), (IV), (V), (VI) or (VII) mayform stable pharmaceutically acceptable acid or base salts, and in suchcases administration of a compound as a salt may be appropriate.Examples of acid addition salts include acetate, adipate, ascorbate,benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate,camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate,diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate,hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate,malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate,nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate,diphosphate, picrate, pivalate, propionate, quinate, salicylate,stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate(p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples ofbase salts include ammonium salts; alkali metal salts such as sodium,lithium and potassium salts; alkaline earth metal salts such asaluminum, calcium and magnesium salts; salts with organic bases such asdicyclohexylamine salts and N-methyl-D-glucamine; and salts with aminoacids such as arginine, lysine, ornithine, and so forth. Also, basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkylsulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl halides; arylalkylhalides such as benzyl bromide and others. Non-toxicphysiologically-acceptable salts are preferred, although other salts maybe useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

Compounds of Formulae (I), (II), (III), (IV), (V), (VI) or (VII) haveone or more chiral centers, and it is to be understood that theapplication encompasses all such stereoisomers, including enantiomersand diastereoisomers. Thus, it is to be understood that, insofar ascertain of the compounds of Formulae (I), (II), (III), (IV), (V), (VI)or (VII) may exist in optically active or racemic forms by virtue of oneor more asymmetric carbon atoms, the application includes in itsdefinition any such optically active or racemic form which possesses theabove-mentioned activity. The present application encompasses all suchstereoisomers having activity as herein defined.

The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Racemates may be separated into individual enantiomersusing known procedures (see, for example, Advanced Organic Chemistry:3rd Edition: author J. March, p 104-107). A suitable procedure involvesformation of diastereomeric derivatives by reaction of the racemicmaterial with a chiral auxiliary, followed by separation, for example bychromatography, of the diastereomers and then cleavage of the auxiliaryspecies. Similarly, the above-mentioned activity may be evaluated usingthe standard laboratory techniques referred to hereinafter.

Thus, throughout the specification, where reference is made to thecompound of Formulae (I), (II), (III), (IV), (V), (VI) or (VII), it isto be understood that the term compound includes isomers, mixtures ofisomers, and stereoisomers that are FLAP inhibitors.

Stereoisomers may be separated using conventional techniques, e.g.chromatography or fractional crystallisation. The enantiomers may beisolated by separation of a racemate for example by fractionalcrystallisation, resolution or HPLC. The diastereoisomers may beisolated by separation by virtue of the different physical properties ofthe diastereoisomers, for example, by fractional crystallisation, HPLCor flash chromatography. Alternatively particular stereoisomers may bemade by chiral synthesis from chiral starting materials under conditionswhich will not cause racemisation or epimerisation, or byderivatisation, with a chiral reagent.

When a specific stereoisomer is provided (whether provided byseparation, by chiral synthesis, or by other methods) it is favorablyprovided substantially isolated from other stereoisomers of the samecompound. In one aspect, a mixture containing a particular stereoisomerof a compound of Formulae (I), (II), (III), (IV), (V), (VI) or (VII),may contain less than 30%, particularly less than 20%, and moreparticularly less than 10% by weight of other stereoisomers of the samecompound. In another aspect, a mixture containing a particularstereoisomer of a compound of Formulae (I), (II), (III), (IV), (V), (VI)or (VII), may contain less than 6%, particularly less than 3%, and moreparticularly less than 2% by weight of other stereoisomers of thecompound. In another aspect, a mixture containing a particularstereoisomer of a compound of Formulae (I), (II), (III), (IV), (V), (VI)or (VII), may contain less than 1%, particularly less than 0.5%, andmore particularly less than 0.3%, and still more particularly less 0.1%by weight of other stereoisomers of the compound.

It is to be understood that, insofar as certain of the compounds ofFormulae (I), (II), (III), (IV), (V), (VI) or (VII), defined above mayexist in tautomeric forms, the application includes in its definitionany such tautomeric form which possesses the above-mentioned activity.Thus, the disclosure relates to all tautomeric forms of the compounds ofFormulae (I), (II), (III), (IV), (V), (VI) or (VII), whether explicitlydetailed in the specification or not.

It is also to be understood that certain compounds of Formulae (I),(II), (III), (IV), (V), (VI) or (VII), and pharmaceutically saltsthereof, can exist in solvated as well as unsolvated forms such as, forexample, hydrated and anhydrous forms. It is to be understood that thecompounds herein encompass all such solvated forms. For the sake ofclarity, this includes both solvated (e.g., hydrated) forms of the freeform of the compound, as well as solvated (e.g., hydrated) forms of thesalt of the compound.

For the sake of clarity, it should be understood that the atoms of thecompounds of Formulae (I), (II), (III), (IV), (V), (VI) or (VII), and ofany of the examples or embodiments disclosed herein, are intended toencompass all isotopes of the atoms. For example, H (or hydrogen)includes any isotopic form of hydrogen including ¹H, ²H (D), and ³H (T);C includes any isotopic form of carbon including ¹²C, ¹³C, and ¹⁴C; Oincludes any isotopic form of oxygen including ¹⁶O, ¹⁷O and ¹⁸O; Nincludes any isotopic form of nitrogen including ¹³N, ¹⁴N and ¹⁵N; Pincludes any isotopic form of phosphorous including ³¹P and ³²P; Sincludes any isotopic form of sulfur including ³²S and ³⁵S; F includesany isotopic form of fluorine including ¹⁹F and ¹⁸F; Cl includes anyisotopic form of chlorine including ³⁵Cl, ³⁷Cl and ³⁶Cl; and the like.In one aspect, the compounds of Formulae (I), (Ia), (II), (III), (IV) or(V) include isotopes of the atoms covered therein in amountscorresponding to their naturally occurring abundance. However, incertain instances, it may be desirable to enrich one or more atom in aparticular isotope which would normally be present in a lower abundance.For example, ¹H would normally be present in greater than 99.98%abundance; however, in one aspect, a compound of any formula presentedherein may be enriched in ²H or ³H at one or more positions where H ispresent. In another aspect, when a compound of any formula presentedherein is enriched in a radioactive isotope, for example ³H and ¹⁴C, thecompound may be useful in drug and/or substrate tissue distributionassays. It is to be understood that the present application encompassesall such isotopic forms.

The present application further provides a process for the preparationof a compound of formula (I) as defined above which comprises reactionSchemes 1-10.

Method of Preparation

Reactions in Schemes 1-10 illustrate synthetic routes to certainmolecules of formula (I), wherein R¹, R², R³, R⁴, and Ring A are asdefined in formula (I), R⁹ is an alkyl group e.g. methyl or ethyl, L₁,L₂, L₃, and L₄ are a leaving groups, e.g., Br, I, OTf, and PG₁ is aprotective group e.g. 2-methyltetrahydro-2H-pyryl.

Reactions in Scheme 1 illustrate two synthetic routes to certainmolecules of formula (I).

A compound of formula (3) may be reacted with a compound of formula (4)to give a compound of formula (2), or a compound of formula (3) may bereacted with a compound of formula (5) to give a compound of formula(I). Either reaction may be performed in the presence of a base, e.g.K₂CO₃ or Na₂CO₃, and may be performed in the temperature interval fromrt to reflux in an organic solvent, such as dioxane or DMF, which may bemixed with H₂O. The reaction may be catalysed by a palladium reagent,such as Pd(dtbpf)Cl₂ or Pd(dppf)Cl₂. A compound of formula (2), may betreated with acid e.g. HCl in an organic solvent e.g. MeOH or dioxaneoptionally in the presence of water, in a temperature interval from 0°C.-10° C., to deliver a compound of formula (I).

Reactions in Scheme 2 illustrate two synthetic routes to certainmolecules of formula (I).

A compound of formula (6), may be formed by reacting a compound offormula (7), with an ammonia synthetic equivalent, e.g. NH₄Cl, and maybe performed in the temperature interval from rt to reflux in an inertorganic solvent, such as DMF, EtOAc, dichloroethane or NMP, and in thepresence of a base e.g. Et₃N, DIPEA or DMAP. The reaction may befacilitated by a coupling reagent, such as HATU, TBTU or T3P. Then, acompound of formula (6), may be reacted with a compound of formula (8).The reaction may be performed in the presence of a base, e.g. Cs₂CO₃ orNaOt-Bu, and may be performed in the temperature interval from rt toreflux in an organic solvent, such as dioxane. The reaction may becatalyzed by a suitable Pd reagent, such as or Pd(dppf)Cl₂ or Pd(OAc)₂using a suitable ligand e.g. XantPhos, to deliver a compound of formula(I).

Alternatively, a compound of formula (7), may be reacted with a compoundof formula (9), which reacation may be performed in the temperatureinterval from rt to reflux in an inert organic solvent, such as DMF,EtOAc, dichloroethane or NMP, and in the presence of a base e.g. Et₃N,DIPEA or DMAP. The reaction may be facilitated by a coupling reagent,such as HATU, TBTU or T3P to deliver a compound of formula (I).

Reaction in Scheme 3 illustrates a synthetic route to certain moleculesof formula (3).

A compound of formula (10), may be reacted with a compound of formula(11), and may be performed in the temperature interval from rt to refluxin an inert organic solvent, such as DMF, EtOAc, dichloroethane or NMP,and in the presence of a base e.g. Et₃N, DIPEA or DMAP. The reaction maybe facilitated by a coupling reagent, such as HATU, TBTU or T3P todeliver a compound of formula (3).

Reactions in Scheme 4 illustrate two synthetic routes to certainmolecules of formula (7).

A compound of formula (10) may be reacted with a compound of formula (4)or formula (5). The reaction may be performed under conditions describedfor the analogous reactions described in Scheme 1.

Reactions in Scheme 5 illustrate a synthetic route to certain moleculesof formula (I).

A compound of formula (31), may be formed by reacting a compound offormula (13), with a compound of formula (8), (9) or (11), described inSchemes 2 and 3, using the same or similar conditions as described forthe reactions of compounds (7) or (10) in Scheme 2 and Scheme 3.

A compound of formula (32), may be formed by reacting a compound offormula (31) with a compound of formula (4) or (5), described in Scheme1, using the same or to similar conditions as described for thereactions of compound (3) in Scheme 1.

A compound of formula (I) may be formed by reacting either a compound offormula (31) or a compound of formula (32) using the same or similarconditions as described for the reactions transforming a compound offormula (13) to a compound of formula (10) in Scheme 5.

Reactions in Scheme 6 illustrate a synthetic route to certain moleculesof formula (12).

A compound of formula (15), may be formed by reacting a compound offormula (16), with a preformed metallo anion e.g. a lithium anion, of acompound of formula (17). The reaction may be performed in an organicsolvent such as e.g. THF, and may be performed at a suitable temperaturesuch as below −70° C. It may also be formed using synthetic proceduresdescribed in the literature e.g. Synlett 12 (2004) 2165-2166 orTetrahedron 67 (2011) 3881-3886.

A compound of formula (14) may be formed by treating a compound offormula (15) with a base, e.g. Et₃N, and may be performed in an organicsolvent e.g. dioxan. The reaction may be performed at elevatedtemperatures e.g. 60° C. A compound of formula (14) may be obtainedcommercially or may be formed in analogy to synthetic proceduresanalogous to those described in the literature e.g. Synlett 12 (2004)2165-2166 or J. Org. Chem. 71 (2006) 6254-6257.

A compound of formula (12) may be formed by reacting a compound offormula (14), with a compound of formula (18). The reaction may beperformed in an inert organic solvent e.g. toluene and may be performedin a temperature interval of rt to 220° C. and may optionally beperformed in the presence of a stabilizer e.g. hydroquinon or may beperformed in a temperature interval of −30° C. to rt, optionally in thepresence of a catalyst, e.g. a Lewis acid such as AlCl₃.

Reactions in Scheme 7 illustrate a synthetic route to certain moleculesof formula (10).

A compound of formula (20) may be formed by reacting a compound offormula (21) with a chlorinating agent e.g. SOCl₂ in an organic solvente.g. DCM and in a temperature interval from −20° C. to reflux, andoptionally in the presence of a catalyst e.g. DMF, or by using othermethods described in the literature and known to person skilled in theart.

A compound of formula (19) could be formed by reacting a compound offormula (20), with a compound of formula (22). The reaction may beperformed in the presence of a catalyst e.g. a Lewis acid catalyst e.g.AlCl₃ and optionally it may be performed in the presence of an inertorganic solvent e.g. DCM and it may be performed in a temperatureinterval of 0° C. to 100° C.

A compound of formula (10) could be formed by reacting a compound offormula (19) with a base, e.g. NaOH or LiOH in an organic solvent e.g.THF or MeOH, or mixtures thereof, and optionally in the presence ofwater. The reaction may be performed in a temperature interval from 0°C. to reflux.

The reaction in Scheme 8 illustrates a synthetic route to certainmolecules of formula (23), wherein X₁ and X₂ are as described in formula(II), X₅ is optionally and independently selected from e.g. H, NO₂ orNHPG₂; wherein PG₂ is a protective group, e.g. tert-butylcarbamate, X₆is independently selected from an heteroatom, e.g. N, O or S, and n is 1or 2.

A compound of formula (23) may be formed by reacting a compound offormula (24), with a compound of formula (25), wherein L₄ is a leavinggroup, e.g. an halide or a sulfonyl ester e.g. OTf, in the presence of abase, e.g. K₂CO₃, and in the presence of an organic solvent, e.g. MeCNor DMF, and the reaction may be performed in a temperature interval from0° C. to reflux.

Reactions in Scheme 9 illustrate a synthetic route to certain moleculesof formula (26), wherein X₆ and n are defined in Scheme 8.

A compound of formula (28), may be formed by reacting a compound offormula (27), with a nitrite source e.g. a nitrite salt e.g. NaNO₂, in asolvent e.g. water, and in the presence of an acid e.g. HCl or CH₃CO₂H.The reaction may be performed in a temperature interval from −5° C. tort. A compound of formula (29), may be formed by reacting a compound offormula (28), with an acid anhydride e.g. trifluoroacetic anhydride, inan organic solvent, e.g. THF, and in a temperature interval from −5° C.to rt. A compound of formula (26), may be formed by reacting a compoundof formula (29), with an alkynyl ester e.g. an ethyl propynoate or amethyl propynoate, in an organic solvent e.g. xylene or o-xylene. Thereaction may be performed at elevated temperatures e.g. from rt toreflux.

Reactions in Scheme 10 illustrates a synthetic route to certainmolecules of formula (30), wherein R⁸ is optionally selected from H oran alkyl group, e.g. methyl, and X₅ is independently selected from e.g.H, NO₂ or NHPG₂.

A compound of formula (33), wherein L₄ is as defined in scheme 8, may beformed by reacting a compound of formula (31), with a compound offormula (32) in the presence of a base, e.g. K₂CO₃, and in the presenceof an organic solvent, e.g. MeCN or DMF, and the reaction may beperformed in a temperature interval from 0° C. to reflux.

A compound of formula (30), may be formed by reacting a compound offormula (33), with a primary amine, e.g. ammonia, or an alkylamine, e.g.ammonia, ammonia hydrate or methylamine, in an organic solvent, e.g.MeCN or THF, and the reaction may be performed in a temperature intervalfrom 0° C. to reflux.

Various permutations of Ring A can be purchased or synthesized usingstandard reaction conditions.

It is understood that organic reactions described herein are performedaccording to laboratory practice known to person skilled in the art. Itis understood that some of the reactions described herein may optionallybe performed in different orders than laid out herein. It is understoodthat chiral isomers of compounds described herein can be resolved at anystage in the synthetic process using chiral resolving agents describedin the literature and known to person skilled in the art or using chiralchromatography methods described in the literature and known to personskilled in the art or as described further in the Examples.

It is understood that additional protective groups may optionally beneeded in some of the steps described above, and it is furtherunderstood that a deprotection step therefore optionally may beperformed, using methods described in the literature and well known toperson skilled in the art. The protection and deprotection of functionalgroups is described in ‘Protective Groups in Organic Synthesis’ 2^(nd)Ed, E. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991) and‘Protecting Groups’, P. J. Kocienski, Georg Thieme Verlag (1994), whichpublication is incorporated herein by reference.

Medical and Pharmaceutical Use

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII)may be useful in the prevention or treatment of cardiovascular diseasein a mammal, particularly a human. Cardiovascular disease includes, butis not limited to, conditions associated with cardiac dysfunction and/ormicrovascular dysfunction and/or macrovascular pathology, such asatherosclerosis, arteriosclerosis, coronary artery disease includingstable and high risk coronary artery disease (defined as recent acutecoronary syndrome (ACS) or by biomarkers of microvascular and cardiacdysfunction), myocardial infarction, restenosis followingrevascularization procedures, heart failure, abdominal aortic aneurysm(AAA), peripheral artery disease (PAD) including erectile dysfunctiondue to vascular disease, stroke, transient ischemic attack (TIA) andreversible ischemic neurologic disease (RIND), multi-infarct dementiaand renal arterial disease.

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII)may be useful in the prevention or treatment of patients with remainingrisk for a cardiovascular event despite standard of care (SoC)treatment, such as, but not limited to, lipid lowering statins,anti-platelets, ACS inhibitors and beta blockers.

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII)may be useful in the prevention or treatment of chronic kidney disease.

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII)may be useful in the prevention or treatment of type II diabetesmellitus and complications of type II diabetes mellitus in a mammal,particularly a human. This includes and is not restricted to, diabeticmicro and macrovascular pathology, neuropathy and nephropathy.

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII)may be useful in the prevention or treatment of respiratory inflammatorydisease and complications associated with respiratory inflammatorydisease in a mammal, particularly a human.

Respiratory inflammatory disease includes, but is not limited to asthma,chronic obstructive pulmonary disease, emphysema and rhinitis.

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII)may be useful in the prevention or treatment of renal inflammatory andvascular diseases and complications associated with renal disease in amammal, particularly a human. Renal inflammatory and vascular diseaseincludes, but is not limited to chronic kidney disease, drug and toxininduced nephrotoxicity, glomerulonephritis, nephrotic syndrome, IgAnephritis, reflux nephropathy, focal segmental glomerulosclerosis,Henoch-Schonleins purpura, and diabetic nephropathy.

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII)may be useful in the prevention or treatment of non-alcoholic fattyliver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Treatment with the compounds of Formulae (I), (II), (III), (IV), (V),(VI) and (VII) may lower the cardiovascular and/or cerebrovascularand/or renal and/or peripheral arterial disease morbidity and mortalityassociated with cardiac dysfunction and/or microvascular dysfunctionand/or macrovascular pathology due to their anti-inflammatory propertiesand influence on vasoactive mechanisms.

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII)may serve to prevent or reduce the risk of developing cardiacdysfunction and/or microvascular dysfunction and/or macrovascularpathology, as well as for halting or slowing the progression and/orpromoting the regression of atherosclerotic cardiovascular disease onceit has become clinically evident, comprising the administration of aprophylactically or therapeutically effective amount, as appropriate, ofa compound of formula (I) to a mammal, including a human, who is at riskof developing atherosclerosis or who already has atheroscleroticcardiovascular disease.

Compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII) may beuseful in preventing or reducing the incidence or severity of acuteevents related to atherosclerotic plaque rupture or erosion, including,but not limited to, myocardial infarction, unstable angina and stroke.

Compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII) may beuseful in preventing or reducing the incidence or severity of acuteevents by improving microvascular function, macrovascular pathologyand/or cardiac function.

Compounds of Formulae (I), (II), (III), (IV), (V), (VI) and (VII) may beuseful in preventing or reducing the progression of abdominal aorticaneurysms (AAA) and incidence of rupture.

For the avoidance of doubt, as used herein, the term “treatment”includes therapeutic and/or prophylactic treatment. “Treatment” alsoincludes administration of a compound of Formulae (I), (II), (III),(IV), (V), (VI) or (VII) in order to alleviate symptoms ofcardiovascular disease (including coronary artery disease and high riskcoronary artery disease) and/or to lessen the severity of, orprogression of, the same.

The compounds disclosed herein may be thus indicated both in thetherapeutic and/or prophylactic treatment of these conditions.

The compounds disclosed herein may have the advantage that they may bemore efficacious, be less toxic, be more selective, be more potent,produce fewer side effects, be more easily absorbed, and/or have abetter pharmacokinetic profile (e.g. higher oral bioavailability and/orlower clearance), than compounds known in the prior art.

Combination Therapy

The compounds of any one of Formulae (I), (II), (III), (IV), (V), (VI)or (VII), or a pharmaceutically acceptable salt thereof, may also beadministered in conjunction with other compounds used for the treatmentof the above conditions.

In another embodiment, there is a combination therapy wherein a compoundof any one of Formulae (I), (II), (III), (IV), (V), (VI) or (VII), or apharmaceutically acceptable salt thereof, and a second active ingredientare administered concurrently, sequentially or in admixture, for thetreatment of one or more of the conditions listed above. Such acombination may be used in combination with one or more further activeingredients.

Compounds described herein may be of use in treating cardiovascular,metabolic and renal disease in combination with agents that are

-   -   cardiac therapies,    -   anti-hypertensives,    -   diuretics,    -   peripheral vasodilators,    -   lipid modifying agents,    -   anti-diabetic,    -   anti-inflammatory    -   anti-coagulant    -   anti-platelet

Examples of the above include, but are not restricted to, digitalisglycosides, anti-arrhythmics, calcium channel antagonists, ACEinhibitors, angiotensin receptor blockers (e.g. candesartan), endothelinreceptor blockers, P3-blockers, thiazide diuretics, loop diuretics,cholesterol synthesis inhibitors such as statins (e.g. Rosuvastatin),cholesterol absorption inhibitors, cholesterylester transfer protein(CETP) inhibitors, anti-diabetic drugs such as insulin and analogues,GLP-1 analogues, sulphonamides, dipeptidyl peptidase 4 inhibitors,thiazolidinediones, SGLT-2 inhibitors, and anti-inflammatory drugs suchas NSAID's and CCR2 antagonists, anti-coagulants such as heparins,thrombin inhibitors and inhibitors of factor Xa, platelet aggregationinhibitors (e.g., P2Y12 antagonists or ticagrelor) and neprilysininhibitors (e.g. Sacubitril).

When used in a combination therapy, it is contemplated that thecompounds of any one of Formulae (I), (II), (III), (IV), (V), (VI) or(VII), or a pharmaceutically acceptable salt thereof, and the otheractive ingredients may be administered in a single composition,completely separate compositions, or a combination thereof. It also iscontemplated that the active ingredients may be administeredconcurrently, simultaneously, sequentially, or separately. Theparticular composition(s) and dosing frequency(ies) of the combinationtherapy will depend on a variety of factors, including, for example, theroute of administration, the condition being treated, the species of thepatient, any potential interactions between the active ingredients whencombined into a single composition, any interactions between the activeingredients when they are administered to the animal patient, andvarious other factors known to physicians, and others skilled in theart.

Administration

There is provided a method of treatment of a condition where inhibitionof FLAP is required, which method comprises administration of atherapeutically effective amount of a compound of Formulae (I), (II),(III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable saltthereof, to a person suffering from, or susceptible to, such acondition.

The compounds of Formulae (I), (II), (III), (IV), (V), (VI) or (VII), ora pharmaceutically acceptable salt thereof, will normally beadministered via the oral, parenteral, intravenous, intramuscular,subcutaneous or in other injectable ways, buccal, rectal, vaginal,transdermal and/or nasal route and/or via inhalation, in the form ofpharmaceutical preparations comprising the active ingredient or apharmaceutically acceptable salt or solvate thereof, or a solvate ofsuch a salt, in a pharmaceutically acceptable dosage form. Dependingupon the disorder and patient to be treated and the route ofadministration, the compositions may be administered at varying doses.

Suitable daily doses of the compounds of Formulae (I), (II), (III),(IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof,in therapeutic treatment of humans are about 0.0001-100 mg/kg bodyweight, preferably 0.01-30 mg/kg body weight.

Oral formulations are preferred particularly tablets or capsules whichmay be formulated by methods known to those skilled in the art toprovide doses of the active compound in the range of 0.1 mg to 1000 mgfor example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg and500 mg.

According to a further aspect there is thus provided a pharmaceuticalcomposition including any of the compounds of Formulae (I), (II), (III),(IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof,in admixture with pharmaceutically acceptable adjuvants, diluents and/orcarriers.

Biological Tests

The following test procedures may be employed:

FLAP Binding Assay (Test A)

Compounds were tested in a competition binding assay using ³H-MK591 astracer. (Preparation of MK-591 is described in Bioorg. Med. Chem. Lett.1999, 9, 2391). A 100,000×g pellet from COS-7 cells stably transfectedwith a plasmid expressing human ALOX5AP was the source of FLAP. Membranepellets were resuspended in buffer (100 mM Tris-HCl, 0.05% Tween-20, 140mM NaCl, 2 mM EDTA, 0.5 mM DTT, 5% Glycerol, pH 7.5) to give a finalprotein concentration of 12 mg/mL (2 μg/well). To perform assays, 1.4 μLcompounds were dispensed into 96-well plates in 3-fold dilution seriesin triplicate. 84 μL radioligand (25000 CPM, 2 nM final concentration inassay) was then added followed by 84 μL membrane suspension andincubation at rt for 60 min. Following filtration, filter plates weredried 12 h at RT (or 50° C. for 1 hour). 50 μL scintillant was thenadded, the filterplates were sealed and radioactivity was measured in amicrobeta counter. Specific binding was defined as total binding minusnon-specific binding. Total binding was defined as ³H-MK591 bound tomembranes in the absence of competitor, non-specific binding was definedas ³H-MK591 in the presence of 0.1 mM MK-591. IC₅₀ values weredetermined by plotting % inhibition versus log compound concentrationand using a one site dose response model. Data for each compound testedis shown in Table 1.

TABLE 1 Example IC₅₀ nM  1 73  2 34  3 37  4 36  5a 2500  5b 22  6 57  76.3  8 45  9 30 10 270 11 82 12 41 13 33 14 400 15 8.6 16 22 17 20 18a3700 18b 28 19 29 20 180 21 230 22 24 23 35 24 8.1 25 25 26 290 27 65 283.9 29 4.8 30 12 31 190 32 170 33 54 34 41 35 83 36 90 37 27 38 20 39 940 70 41 160 42 200 43 140 44 46 45 210 46 86 47 53 48 23 49 44

FLAP Whole Blood Assay (Test B)

Compounds were tested for the inhibition of LTB₄ production in freshhuman whole blood obtained by venapuncture using heparin to preventclotting. 1.5 μL compounds or DMSO carrier were dispensed into the wellsof a 96-well deep-well plate in 3-fold dilution series. 500 μL hepamisedwhole blood was then added followed by incubation at 37° C. for 30 min(method A) or 4 h (method B). 100 μL blood was subsequently transferredin triplicate to pre-dispensed 0.5 μL 2 mM calcium ionophore(calcimycin; A23187) in a second 96-well plate. Following incubation at37° C. for 20 min, the assays were stopped by adding 10 μL of stopsolution (100 mM EGTA, pH 7.4) and the plate was transferred to ice. Theplate was centrifuged at 3000 rpm at 4° C. for 10 min and L plasma wastransferred to a fresh 96 well plate containing 90 μL pre-dispensed EIAassay buffer (0.1 M phosphate buffer+0.1% BSA). LTB₄ was then measuredusing reagents from a commercial EIA (Cayman Chemicals). LTB₄ productionwas defined as the LTB₄ level in the presence of a given concentrationof test compound minus the LTB₄ level in the presence of 50 nM5-[[4-[(2S,4R)-4-hydroxy-2-methyl-tetrahydropyran-4-yl]-2-thienyl]sulfanyl]-1-methyl-indolin-2-one.(Preparation of5-[[4-[(2S,4R)-4-hydroxy-2-methyl-tetrahydropyran-4-yl]-2-thienyl]sulfanyl]-1-methyl-indolin-2-onewas described in Org. Process Res. Dev., 2005, 9, 555-569 or EP623614B1). Inhibition of LTB₄ production was defined as the LTB₄ level in thepresence of a given concentration of test compound expressed as a % ofthe LTB₄ level in the presence of DMSO. IC₅₀ values were determined byplotting % inhibition versus log compound concentration and using a onesite dose response model. Data for each example tested is shown in Table2.

TABLE 2 IC₅₀ nM Example (method A or B)  1 112 (A)  2  60 (B)  3  70 (B) 4 290 (B)  5a ND  5b  95 (B)  6 380 (B)  7  40 (B)  8  35 (B)  9 110(B) 10 340 (B) 11 140 (B) 12 100 (B) 13 260 (B) 14 654 (A) 15  28 (B) 16 41 (B) 17  18 (B) 18a ND 18b 114 (B) 19  80 (B) 20 281 (A) 21 360 (A)22 740 (B) 23 130 (B) 24  18 (B) 25 210 (B) 26 250 (B) 27  55 (B) 28 380(B) 29 330 (B) 30  50 (B) 31 390 (B) 32 915 (B) 33 117 (B) 34  41 (B) 35 79 (B) 36 148 (B) 37  40 (B) 38  69 (B) 39  34 (B) 40 208 (A) 41 272(B) 42 149 (A) 43 904 (B) 44 197 (A) 45 ND 46 170 (A) 47 260 (A) 48 270(A) 49 640 (A) ND = not determined

EXAMPLES

The compounds of the application will now be further explained byreference to the following non limiting examples.

In the examples, high resolution mass spectra were recorded on aMicromass LCT mass spectrometer equipped with an electrospray interface(LC-HRMS). 1H NMR measurements were performed on Varian UNITY plus 400,500 and 600 spectrometers or Varian INOVA 400, 500 and 600 spectrometersor Bruker Avance 400, 500 and 600 spectrometers, operating at 1Hfrequencies of 400, 500 and 600 MHz, respectively. The experiments weretypically recorded at 25° C. Chemical shifts are given in ppm with thesolvent as internal standard. Flash chromatography was performed usingstraight phase flash chromatography on a SP1™ Purification system fromBiotage™ using normal phase silica FLASH+™ (40M, 25M or 12 M) or SNAP™KP-Sil Cartridges (340, 100, 50 or 10) unless otherwise stated. Ingeneral, all solvents used were commercially available and of analyticalgrade. Anhydrous solvents were routinely used for reactions. PhaseSeparators used in the examples are ISOLUTE® Phase Separator columns.The Intermediates and Examples named below were named using ACD/Name12.01 from Advanced Chemistry Development, Inc. (ACD/Labs).

The following abbreviations are used

-   AcOH acetic acid-   aq aqueous-   Boc₂O di-tert-butyl dicarbonate-   DCE dichloroethane-   DCM dichloromethane-   DEA diethylamine-   DIPEA N,N-diisopropylethylamine-   DMAP dimethylaminopyridine-   DME dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DPPA diphenyl phosphorazidate-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   dtbpf 1,1′-bis(ditertbutylphosphino)ferrocene-   EtOAc ethylacetate-   EtOH ethanol-   h hour(s)-   HATU    (dimethylamino)-N,N-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridinyl)methaniminium    hexafluorophosphate-   MeCN acetonitrile-   MeOH methanol-   min minute(s)-   MS mass spectrometer-   NMP N-methyl-2-pyrrolidone-   NMR nuclear magnetic resonanse-   Pd(dppf)Cl₂*DCM 1,1′-bis(di-tert-butylphosphino)ferrocene palladium    dichloride-   rt room temperature-   sat saturated-   SFC supercricica fluid chromatography-   T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide-   TBTU    2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium    tetrafluoroborate-   THF tetrahydrofuran-   TLC thin layer chromatography-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Synthesis of Starting Materials and Intermediates Intermediate 1: (1R,2Rand 1S,2S)-2-[4-(1H-Pyrazol-3-yl)benzoyl]-cyclohexanecarboxylic acid

A mixture of (1R,2R and 1S,2S)-2-(4-bromobenzoyl)cyclohexanecarboxylicacid (200 mg, 0.64 mmol), 1H-pyrazol-3-ylboronic acid (129 mg, 1.16mmol) and Pd(dppf)Cl₂*DCM (46.5 mg, 0.06 mmol) and K₂CO₃ (266 mg, 1.93mmol) in dioxane (4 mL)/water (4 mL) was heated at reflux for 90 min.The mixture was diluted with EtOAc and water. The phases were separatedand the water phase was washed with EtOAc. The combined water layerswere acidified with HCl (6 M) until pH was approximately 4-5 and theproduct was extracted into EtOAc. The organic layer was dried overNa₂SO₄, filtered and evaporated to give the title compound (240 mg) as abrown solid.

MS m/z 299 (M+H)⁺

Intermediate 2:4-({[(1R,2R)-2-(4-Bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide

T3P, (50% in EtOAc, 800 μl, 1.34 mmol) was added to a solution of(1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (200 mg, 0.64mmol), 4-amino-1-methyl-1H-pyrazole-5-carboxamide (180 mg, 1.28 mmol)and Et₃N (356 μl, 2.57 mmol) in dry EtOAc (3 mL) and the reactionmixture was heated at 80° C. for 4 h in a microwave reactor. The mixturewas diluted with EtOAc and washed twice with NaHCO₃ (sat, aq) and brine.The organic phase was dried using a phase separator and the solventevaporated. The compound was purified by preparative HPLC on a XBridgeC18 column (10 μm 250×19 ID mm) using a gradient of 30-85% MeCN inH₂O/MeCN/NH₃ (95/5/0.2) buffer system at pH10 as mobile phase. Thedesired fractions were collected and the solvent evaporated to give thetitle compound (130 mg, 47%).

¹H NMR (400 MHz, CDCl3) δ 1.2-1.54 (m, 3H), 1.70 (ddd, 1H), 1.81-1.98(m, 2H), 2.02-2.17 (m, 2H), 2.78-2.94 (m, 1H), 3.56-3.73 (m, 1H), 4-4.1(m, 3H), 6.11 (d, 2H), 7.55-7.65 (m, 3H), 7.81 (d, 2H), 8.00 (s, 1H)

MS m/z 433.1 [M+H]⁺

Intermediate 3:3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step 1—3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

3-Methyl-1H-pyrazole (2 mL, 24.8 mmol) was dissolved in3,4-dihydro-2H-pyran (6.8 mL, 74.5 mmol). Trifluoroacetic acid (0.134mL, 1.74 mmol) was added and the clear solution was warmed to 75° C. for18 h. The reaction mixture was diluted with Et₂O and the organic phasewas washed with NaHCO₃ (sat, aq), water and brine, filtered using aphase separator and concentrated in vacuo. The residue was purified byflash chromatography (10%→20% of EtOAc in heptane) to give the subtitlecompound. (2.4 g, 58%, 70% correct isomer)

¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, 1H), 7.40 (s, 0.3H), 6.04 (d, 1H),6.00 (s, 0.3H), 5.21-5.28 (m), 3.94-4.09 (m), 3.57-3.68 (m), 2.47 (s,OH), 2.31 (s, 1H), 2.26 (s, 3H), 1.9-2.16 (m), 1.59-1.75 (m).

Step2—3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

n-Butyllithium (6.1 mL, 15.2 mmol, 2.5M in THF) was added during 10 minto a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.4g, 14.4 mmol) in THF (20 mL) at −78° C. During a period of 15 mintripropan-2-yl borate (3.7 mL, 15.9 mmol) was added dropwise at −78° C.and the reaction mixture was stirred for 15 min, where after it wasallowed to reach rt. 2,3-Dimethylbutane-2,3-diol (1.88 g, 15.9 mmol) wasadded followed by AcOH (1.65 mL, 28.9 mmol) and the reaction mixture wasstirred at rt over night. The reaction mixture was diluted with heptaneand the organic phase was washed with NH₄Cl (aq), NaHCO₃ (aq) and brine,filtered using a phase separator and concentrated. The residue wasdiluted with heptane and concentrated to give the title compound (3.86,91%).

MS m/z 293.2 [M+H]⁺

Intermediate 4:1-Methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide

Step1—4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide

Et₃N (5.5 mL, 39.7 mmol) and T3P (50% in EtOAc, 12 mL, 20.2 mmol) wasadded to a solution of (1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylicacid (3 g, 9.6 mmol), 4-amino-1-methyl-1H-pyrazole-5-carboxamide (2.7 g,19.3 mmol) and Et₃N (5.5 mL, 39.7 mmol) in EtOAc (45 mL) and thereaction mixture was heated at 75-80° C. for 2 h. The mixture wasdiluted with EtOAc (100 mL) and washed four times with NaHCO₃ (sat, aq)and twice with NH₄Cl (sat, aq) and water. The organic phase was driedusing a phase-separator and the solvent was removed under vacuum. Theresidue was dissolved in EtOAc and the organic phase was washed twicewith NaHCO₃ (sat, aq) and twice with NH₄Cl (sat, aq) and finally water.The organic phase was dried using a phase separator, and the solvent wasremoved under vacuum to give the crude subtitle compound (3.55 g) as acream-colored residue.

¹H NMR (500 MHz, CDCl₃) δ 1.31-1.56 (m, 3H), 1.70 (qd, 1H), 1.81-1.97(m, 3H), 2.07-2.15 (m, 1H), 2.81-2.93 (m, 1H), 3.61-3.71 (m, 1H), 4.04(s, 3H), 6.29 (s, 2H), 7.51-7.69 (m, 3H), 7.81 (d, 2H), 8.08 (s, 1H)

MS m/z 433 [M+H]⁺

Step2—1-Methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide

3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 4.2 g, 14.37 mmol) and a solution of K₂CO₃ (3.19 g,23.08 mmol) in water (35 mL) was added to a solution of4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]-carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 2, 2.5 g, 5.77 mmol) in dioxane (35 mL) under anatmosphere of nitrogen. Pd(dtbpf)Cl₂ (0.371 g, 0.58 mmol) was added andthe resulting mixture was heated at 70-80° C. for 20 min and then at 80°C. for 30 min. The reaction mixture was diluted with EtOAc (200 mL) andwashed with brine (sat). The aqueous phase was extracted twice withEtOAc and the combined organic phase was dried using a phase separatorand concentrated. The residue was purified by flash chromatography(50→100% EtOAc in heptane, then 100% EtOAc) to give the title compound(2.15 g, 72%).

¹H NMR (500 MHz, CDCl₃) δ 1.29-1.46 (m, 2H), 1.75 (dq, 3H), 1.85-1.98(m, 2H), 2.02 (s, 1H), 2.04 (s, 3H), 2.14 (d, 2H), 2.32 (s, 3H),2.62-2.45 (m, 1H), 2.93 (t, 1H), 3.59 (td, 1H), 3.7-3.85 (m, 1H),4.02-4.1 (m, 3H), 5.10 (t, 1H), 6.16 (s, 1H), 6.22-6.45 (bs, 2H), 7.60(dd, 3H), 8.04 (dd, 2H), 8.13-8.33 (bs, 1H).

MS m/z 519.4 [M+H]⁺

Intermediate 5: Methyl4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxylate

T3P (50% in EtOAc, 1.9 mL, 3.2 mmol) was added to a solution of(1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (674 mg, 2.17mmol), methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate hydrochloride(457 mg, 2.38 mmol) and Et₃N (0.63 mL, 4.5 mmol) in EtOAc (9 mL) and thereaction mixture was heated at 80° C. for 2 h and then at rt for 2 days.The reaction mixture was washed with NaHCO₃ (sat, aq), NH₄Cl (sat. aq)and brine. The organic phase was dried using a phase separator and thesolvent was removed under vacuum. The residue was purified by flashchromatography (50% of EtOAc) to give the title compound (640 mg 66%).

¹H NMR (500 MHz, CDCl₃) δ 1.26-1.35 (m, 1H), 1.35-1.49 (d, 2H), 1.57-1.7(m, 1H), 1.88 (dd, 2H), 1.98-2.04 (m), 2.09-2.18 (m, 1H), 2.87-2.99 (m,1H), 3.6-3.69 (m, 1H), 3.85 (s, 3H), 3.96 (s, 3H), 7.57 (d, 2H), 7.84(d, 2H), 8.04 (s, 1H), 9.09 (s, 1H).

MS m/z 448 [M+H]⁺

Intermediate 6:4-({[(1R,2R)-2-(4-Bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxamide

Step1—4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxylicacid

LiOH (1 M aq) (3 mL, 3.00 mmol) was added to a solution of methyl4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxylate(Intermediate 5, 640 mg, 1.43 mmol) in THF (3 mL) and MeOH (3 mL) andthe reaction mixture was stirred at rt for 2 h. The reaction mixture wasconcentrated and HCl (3.8 M, aq) (1 mL) was added followed by water (20mL). The water phase was extracted twice with EtOAc and the combinedorganic phase was filtered using a phase separator and concentrated togive the subtitle compound (640 mg, 103%).

MS m/z 432 [M−H]⁻

Step2—4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxamide

DIPEA (0.68 mL, 3.9 mmol), TBTU (749 mg, 2.33 mmol) and ammoniumchloride (139 mg, 2.59 mmol) was added to a solution of4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]-carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxylicacid (563 mg, 1.30 mmol) in DMF (5 mL) and the reaction mixture wasstirred at rt overnight. The reaction mixture was diluted with DMSO andpurified by preparative HPLC on a XBridge C18 column (10 μm 250×50 IDmm) using a gradient of 5-75% MeCN in H₂O/MeCN/NH₃ (95/5/0.2) buffersystem as mobile phase. The desired fractions were collected,concentrated and extracted with EtOAc. The organic phase was filteredusing a phase separator and concentrated to give the title compound (280mg, 50%).

¹H NMR (500 MHz, DMSO-d₆) δ 1.16 (dd, 1H), 1.33-1.55 (m, 3H), 1.67-1.85(m, 2H), 1.90 (d, 1H), 2.02 (d, 1H), 2.81-2.92 (m, 1H), 3.63-3.71 (m,1H), 3.79 (s, 3H), 7.46 (s, 1H), 7.64 (s, 1H), 7.73 (d, 2H), 7.93 (d,2H), 8.04 (s, 1H), 9.75 (s, 1H).

Intermediate 7: (1R,2R and1S,2S)-2-(4-bromobenzoyl)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)cyclohexanecarboxamide

T₃P (50% in EtOAc, 1.6 g, 4.9 mol) was added to a mixture of (1R,2R and1S,2S)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (1.3 g, 4.1 mol),4-amino-1-methyl-1H-pyrazole-3-carbonitrile (0.5 g, 4.1 mol) and DMAP(1.0 g, 8.2 mol) in DCE (10 mL) and the reaction mixture was heated in amicrowave reactor at 100° C. for 1 h. The mixture was cooled to rt anddiluted with DCM. The organic phase was washed with brine, dried andconcentrated and the residue was purified by flash chromatography(petroleum ether:EtOAc, 3:1) to give the title compound (0.4 g, 24%) asa white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.49-1.39 (m, 3H), 1.76-1.69 (m, 1H),1.95-1.86 (m, 2H), 2.12-2.03 (m, 2H), 2.91-2.84 (m, 1H), 3.69-3.62 (m,1H), 3.85 (s, 3H), 7.59 (d, 2H), 7.64 (s, 1H), 7.83 (d, 2H), δ 7.99 (s,1H)

Intermediate 8:(1R,2R)-2-{4-[3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxylicacid

K₂CO₃ (4.02 g, 29.05 mmol) and Pd(dtbpf)Cl₂ (0.28 g, 0.36 mmol) wereadded to a solution of (1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylicacid (2.26 g, 7.26 mmol) and3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 3.18 g, 10.89 mmol) dissolved in 1,4-dioxane (40 mL)and water (20 mL). The mixture was evacuated and purged with nitrogenthree times and then heated at 80° C. for 1 h. The mixture was cooled tort and diluted with EtOAc. NaHCO₃ (sat, aq) was added and the mixturewas acidified with KHSO₄ (1 M, aq). The phases were separated and theaqueous phase was extracted twice with EtOAc. The combined organic phasewas dried using a phase separator and the solvent was removed undervacuum. The crude residue was purified by preparative HPLC on a KromasilC8 column (10 μm 250×50 ID mm) using a gradient of 30%-90% MeCN inH₂O/MeCN/AcOH (95/5/0.2) buffer system as mobile phase. The selectedfractions were combined and concentrated under vacuum and the aqueousresidue was extracted twice with DCM. The combined organic phase wasdried using a phase separator and the solvent was removed under vacuumto give the title compound (2.79 g, 97%) as a light brown solid.

¹H NMR (500 MHz, CDCl₃) δ 1.21-1.64 (m, 6H), 1.71-1.94 (m, 4H),2.02-2.12 (m, 2H), 2.23-2.31 (m, 1H), 2.34 (s, 3H), 2.52-2.64 (m, 1H),2.93-3.02 (m, 1H), 3.53-3.66 (m, 2H), 4.11-4.19 (m, 1H), 5.13 (dd, 1H),6.18 (s, 1H), 7.56-7.63 (m, 2H), 8.01-8.07 (m, 2H)

MS m/z 395.3 [M−H]⁻

Intermediate 9: Methyl4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate

Di-tert-Butyl dicarbonate (159 mL, 0.68 mol) was added to methyl4-amino-1H-pyrazole-3-carboxylate (87.6 g, 0.62 mol) and pyridine (100mL, 1.24 mol) in MeOH (1 L) at 10° C. over a period of 15 min. Thereaction mixture was stirred at rt for 5 h. The solvent was removedunder vacuum. The crude product was purified by crystallization fromMeOH (700 mL) to give the title compound (80 g, 53%) as a purple solid.

MS m/z 228 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 1.47 (s, 9H), 3.83 (s, 3H), 7.70-8.20 (m,2H), 13.45 (s, 1H)

Intermediate 10: Methyl1-(2-bromoethyl)-4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate

1,2-dibromoethane (1.97 mL, 22.8 mmol) was added to a solution of methyl4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate (Intermediate9, 5.0 g, 20.7 mmol) and K₂CO₃ (4.3 g, 31.1 mmol) in DMF (50 mL) at 0°C. over a period of 10 min and the reaction mixture was stirred at rtfor 5 h. Water was added to the reaction mixture and the aqueous phasewas extracted with EtOAc. The organic layer was dried over MgSO₄,filtered and evaporated and the crude product was purified by flashchromatography (5%→20% 2-methylpentane in EtOAc). Pure fractions wereevaporated to dryness to give the title compound (2.5 g, 35%) as acolorless oil.

¹H NMR (300 MHz, DMSO-d₆) δ 1.47 (s, 9H), 3.80 (t, 2H), 3.87 (s, 3H),4.79 (t, 2H), 7.86 (s, 1H), 8.24 (s, 1H)

MS m/z 348 [M+H]⁺

Intermediate 11: tert-Butyl(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate

Ammonia hydrate (10 g, 287.2 mmol) was added to a solution of methyl1-(2-bromoethyl)-4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate(Intermediate 10, 10.0 g, 28.7 mmol) in MeCN (100 mL) and the reactionvessel was sealed and heated at 90° C. for 20 h. The solvent was removedunder vacuum and the crude product was purified by flash chromatography,elution gradient (1%→10% DCM in MeOH). Pure fractions were evaporated todryness to give the title compound (6.0 g, 83%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.47 (s, 9H), 3.60 (t, 2H), 4.22 (t, 2H),7.76 (s, 1H), 7.95 (s, 1H), 8.30 (s, 1H)

MS m/z 253 [M+H]⁺

Intermediate 12: 3-Amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onehydrochloride

HCl (g) was added to a solution of tert-butyl(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate(Intermediate 11, 9 g, 35.68 mmol) in MeOH (50 mL) and the reactionmixture was stirred at rt for 2 h. The precipitate was collected byfiltration, washed with EtOAc and dried under vacuum to give the titlecompound (6.00 g, 89%) as a white solid.

MS m/z 153 [M+H]⁺

Intermediate 13:(1R,2R)-2-(4-Bromobenzoyl)-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide

A mixture of 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onehydrochloride (Intermediate 12, 1.0 g, 5.30 mmol) and Et₃N (2.96 mL,21.21 mmol) in DMF (10 mL) was added to a stirred solution of(1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (1.82 g, 5.83 mmol)and HATU (4.03 g, 10.60 mmol) in DMF (10 mL), over a period of 5 min.The reaction mixture was stirred at 50° C. for 15 h. The reactionmixture was diluted to with EtOAc, and washed sequentially with NaHCO₃(sat, aq), brine (sat.), and water. The organic layer was dried overMgSO₄, filtered and evaporated and the crude product was purified byflash chromatography (1%→10% DCM in MeOH). Pure fractions wereevaporated to dryness to give the title compound (1.2 g, 51%) as a whitesolid.

MS m/z 445 [M+H]⁺

Intermediate 14:(1R,2R)-2-{4-[3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide

Pd(dppf)Cl₂*DCM (0.092 g, 0.11 mmol) was added to a solution of(1R,2R)-2-(4-bromobenzoyl)-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(Intermediate 13, 1.0 g, 2.25 mmol),3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 0.984 g, 3.37 mmol) and Na₂CO₃ (0.952 g, 8.98 mmol) indioxane (20 mL) and water (5 mL) over a period of 10 min under nitrogenatmosphere. The reaction mixture was stirred at 90° C. for 3 h. Thesolvent was removed under vacuum and the residue was diluted with EtOAc.The organic phase was washed sequentially with NaHCO₃ (sat, aq), asolution of brine (sat.), and water. The organic layer was dried overNa₂SO₄, filtered and evaporated. The crude product was purified by flashchromatography (10%→50% 2-methylpentane in EtOAc) to give the titlecompound (1.0 g, 84%) as a yellow solid.

MS m/z 531 [M+H]⁺

Intermediate 15: tert-Butyl[1-methyl-5-(methylsulfanyl)-1H-pyrazol-4-yl]carbamate

Et₃N (873 mg, 8.63 mmol) and DPPA (1.19 g, 4.32 mmol) was added to asolution of 1-methyl-5-(methylsulfanyl)-1H-pyrazole-4-carboxylic acid(400 mg, 2.32 mmol) in tert-butanol (15 mL) under inert atmosphere andthe reaction mixture was stirred at 20° C. for 2 h and then heated toreflux for an additional 13 h. The resulting mixture was concentrated invacuo and the residue was dissolved in EtOAc. The organic phase waswashed with water and brine, dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gel columnchromatography (9% EtOAc in petroleum ether) to give the title compound(330 mg, 58%) as a white solid.

MS m/z 244 [M+H]⁺

Intermediate 16: 1-Methyl-5-(methylsulfanyl)-1H-pyrazol-4-aminehydrochloride

HCl (g) was bubbled into a solution of tert-butyl[1-methyl-5-(methylsulfanyl)-1H-pyrazol-4-yl]carbamate (Intermediate 15,1.6 g, 6.58 mmol) in MeOH (30 mL) at 20° C. with stirring for 1 h. Thereaction mixture was concentrated under vacuum to give the titlecompound (1.56 g, crude) as a light yellow solid.

MS m/z 144 [M+H]⁺

Intermediate 17:(1R,2R)-2-(4-Bromobenzoyl)-N-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-4-yl]cyclohexanecarboxamide

HATU (3.8 g, 9.99 mmol) was added to a stirred solution of(1R,2R)-2-[(4-bromophenyl)carbonyl]cyclohexane-1-carboxylic acid (2.3 g,7.39 mmol) in DMF (20 mL) at 0° C. A solution of1-methyl-5-(methylsulfanyl)-1H-pyrazol-4-amine hydrochloride(Intermediate 16, 1.5 g, 8.35 mmol) in DMF (10 mL) and DIPEA (3.24 g,25.07 mmol) was added dropwise to the reaction mixture at 0° C. and thereaction mixture was stirred at rt for 2 h. The reaction mixture wasconcentrated under vacuum and the residue was dissolved in EtOAc. Theorganic phase was washed with NaHCO₃ (sat, aq) and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn (28% EtOAc in petroleum ether) to give the title compound (2.1 g65%) as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.19-1.09 (m, 1H), 1.43-1.31 (m, 3H),1.93-1.73 (m, 3H), 2.11-2.08 (m, 1H), 2.24 (s, 3H), 3.04-2.95 (m, 1H),3.72-3.64 (t, 1H), 3.81 (s, 3H), 7.57 (s, 1H), 7.75-7.72 (d, 2H),7.94-7.91 (d, 2H), 9.42 (s, 1H)

MS m/z 436 [M+H]⁺

Intermediate 18:(1R,2R)-2-(4-Bromobenzoyl)-N-[1-methyl-5-(methylsulfonyl)-1H-pyrazol-4-yl]cyclohexanecarboxamide

3-Chloroperoxybenzoic acid (356 mg, 2.06 mmol) was added in portions at0° C. to a solution of(1R,2R)-2-(4-bromobenzoyl)-N-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-4-yl]cyclohexanecarboxamide(Intermediate 17, 600 mg, 1.4 mmol) in DCM (10 mL). The reaction mixturewas stirred 0° C. for 40 min. 3-Chloroperoxybenzoic acid (356 mg, 2.06mmol) was added in portions at 0° C. to the reaction mixture after whichthe mixture was stirred at rt for 60 min. The reaction mixture wasdiluted with DCM and the organic phase was washed with water and brine,dried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (96% DCM in MeOH) to give thetitle compound (630 mg, 98%) as a white solid.

MS m/z 468 [M+H]⁺

Intermediate 19: tert-Butyl[3-(difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]carbamate

DIPEA (580 mg, 4.49 mmol) was added in portions to a solution of3-(difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (575 mg, 2.99mmol) in tert-BuOH (20 mL) under an atmosphere of nitrogen. DPPA (1.0 g,3.63 mmol) was added dropwise with stirring to the reaction mixture andafter which it was stirred at 80° C. for 12 h. The reaction mixture wasconcentrated under vacuum and the residue was purified by silica gelcolumn chromatography (5%→20% EtOAc in petroleum) to give the titlecompound (630 mg, 80%) as light yellow oil.

MS m/z 264 [M+H]⁺

Intermediate 20: 3-(Difluoromethoxy)-1-methyl-1H-pyrazol-4-aminehydrochloride

HCl(g) was bubbled into a solution of tert-butyl[3-(difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]carbamate (Intermediate19, 500 mg, 1.90 mmol) in EtOAc (20 mL) and the reaction mixture wasstirred at rt for 2 h. The reaction mixture was concentrated undervacuum and the residue was washed with a solution of EtOAc/Petroleumether (5 mL, 1:1) to give the title compound (320 mg, 84%) as a whitesolid.

¹H NMR (300 MHz, CDCl₃) δ 3.77 (s, 3H), 7.32 (t, 1H), 7.95 (s, 1H),10.37 (bs, 2H)

Intermediate 21:(1R,2R)-2-(4-Bromobenzoyl)-N-[3-(difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]cyclohexanecarboxamide

DIPEA (778 mg, 6.02 mmol) and T3P (50% in EtOAc, 1.92 g, 6.03 mmol) wasadded to a solution of (1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylicacid (514 mg, 1.65 mmol) and3-(difluoromethoxy)-1-methyl-1H-pyrazol-4-amine hydrochloride(Intermediate 20, 300 mg, 1.50 mmol) in EtOAc (10 mL) and the reactionmixture was stirred at 75° C. for 2 h. The reaction mixture wasconcentrated under vacuum and the residue was purified by silica gelcolumn chromatography (5%→20% EtOAc in petroleum) to give the titlecompound (360 mg, 52%) as light yellow solid.

MS m/z 456 [M+H]⁺

Intermediate 22: 1-Methyl-4-nitro-1H-pyrazole-3-sulfonyl chloride

Step 1

CuCl2*2H₂O (4.1 g, 24 mmol) was added to a solution of SO₂ (g) in AcOH(32%, aq) (246 g, 3.84 mol) and the reaction mixture was stirred at −10°C. for 1 h in an ice/salt bath with SO₂ gas being bubbled into thereaction mixture.

Step 2

NaNO₂ (6.9 g, 100 mmol) in water (50 mL) was added dropwise during 1 hto a solution of 1-methyl-4-nitro-1H-pyrazol-3-amine (13.5 g, 95 mmol)in AcOH/HCO₂H (5:1, 180 mL) and HCl (12 M, aq) (16 mL) at −10° C. underan atmosphere of nitrogen. The formed yellow solution was added inportions into the preformed solution from Step 1 during 1 h resulting inimmediate evolution of nitrogen. The reaction mixture was stirred for 1h and concentrated under vacuum. The residue was diluted with EtOAc andthe organic phase was washed twice with water and twice with brine. Theorganic layer was dried and concentrated under vacuum to give the titlecompound (15 g, 70%) as a yellow semi-solid.

MS m/z 227 [M+H]⁺

Intermediate 23: 1-Methyl-4-nitro-1H-pyrazole-3-sulfonamide

A solution of 1-methyl-4-nitro-1H-pyrazole-3-sulfonyl chloride(Intermediate 22, 5.1 g, 22.6 mmol) in THF (50 mL) was added dropwiseduring 1 h to a saturated solution of ammonia in THF (200 mL) at rt andthe reaction mixture was stirred at rt for 5 h. The solids formed werecollected by filtration and washed with DCM (100 mL), water (50 mL) andMeOH (50 mL) to give the title compound (2.4 g, 51%) as a white solid.

MS m/z 207 [M+H]⁺

Intermediate 24: 4-Amino-1-methyl-1H-pyrazole-3-sulfonamide

A solution of 1-methyl-4-nitro-1H-pyrazole-3-sulfonamide (Intermediate23, 3.1 g, 15.0 mmol) in MeOH (200 mL). Pd/C (10%, 400 mg) was added andthe reaction mixture was stirred at rt for 6 h under an atmosphere of H₂(g). The solids were filtered out and the reaction mixture wasconcentrated under vacuum. The resulting solids were washed with MeOH(50 mL) to give the title compound (2.1 g, 79%) as a light pink solid.

¹H NMR (300 MHz, DMSO-d₆) δ 3.75 (s, 3H), 4.33 (s, 2H), 7.15 (s, 1H),7.26 (s, 2H)

MS m/z 177 [M+H]⁺

Intermediate 25:(1R,2R)-2-(4-Bromobenzoyl)-N-(1-methyl-3-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide

T₃P (50% in EtOAc, 3.61 g, 5.68 mmol), Et₃N (861 mg, 8.51 mmol) and(1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (500 mg, 1.61 mmol)was added to a solution of 4-amino-1-methyl-1H-pyrazole-3-sulfonamide(Intermediate 24, 884 mg, 5.02 mmol) in EtOAc (50 mL) and the reactionmixture was stirred at 80° C. for 5 h. The reaction mixture was washedwith NaHCO₃ (sat, aq), twice with water and finally twice with brine.The organic layer was dried over Na₂SO₄, filtered and concentrated undervacuum to give the title compound (720 mg, 31%) as a white solid.

MS m/z 469 [M+H]⁺

Intermediate 26: 2,3-Dihydropyrazolo[5,1-b][1,3]oxazole

1,2-Dibromoethane (73.7 g, 392.5 mmol) was added to a solution of1H-pyrazol-3-ol (11 g, 130.83 mmol) and K₂CO₃ (48.3 g, 349.3 mmol) inMeCN (200 mL) at rt and the reaction mixture was heated at 80° C. for 6h. The reaction mixture was filtered and the filtrate was concentratedunder vacuum and purified by flash chromatography (1%→2.5% MeOH in DCM)to give the title compound (4.0 g, 28%) as a yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 4.30 (t, 2H), 5.06 (t, 2H), 5.34 (s, 1H), 7.36(s, 1H)

MS m/z 111 [M+H]⁺

Intermediate 27: 7-Nitro-2,3-dihydropyrazolo[5,1-b][1,3]oxazole

HNO₃ (36.1 mL, 802.3 mmol) and H₂SO₄ (36.1 mL, 676.8 mmol) were addedover a period of 1 h to a solution of2,3-dihydropyrazolo[5,1-b][1,3]oxazole (Intermediate 26, 15.89 g, 144.3mmol) in H₂SO₄ (72 mL) at 0° C. under an atmosphere of nitrogen and thenthe reaction mixture was stirred at rt for 16 h. The reaction mixturewas added to ice water and the aqueous layer was extracted two timeswith DCM. The combined organic layer was dried over Na₂SO₄, filtered andevaporated. The crude product was purified by flash chromatography(0%→100% EtOAc in petroleum ether) to give the title compound (12.5 g,56%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ 4.44 (t, 2H), 5.35 (t, 2H), 7.90 (s, 1H)

MS m/z 156 [M+H]⁺

Intermediate 28: tert-Butyl2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-ylcarbamate

Di-tert-butyl dicarbonate (21.1 g, 96.7 mmol) and Pd—C (2.1 g, 19.7mmol) were added to a solution of7-nitro-2,3-dihydropyrazolo[5,1-b][1,3]oxazole (Intermediate 27, 5 g,32.23 mmol) in MeOH (100 mL) and the reaction mixture was stirred at rtunder an atmosphere of H₂ (1 atm) for 35 h. The reaction mixture wasfiltered, the filtrate was concentrated under vacuum and the crudeproduct was purified by flash chromatography (0%→90% EtOAc in petroleumether) to give the title compound (2.55 g, 35%) as a pale yellow solid.

MS m/z 226 [M+H]⁺

Intermediate 29: 2,3-Dihydropyrazolo[5,1-b][1,3]oxazol-7-aminehydrochloride

HCl (g) was bubbled for 1 h at rt into a solution of tert-butyl2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-ylcarbamate (Intermediate 28,500 mg, 2.22 mmol) in EtOAc (20 mL). The reaction mixture wasconcentrated under vacuum to give the title compound (350 mg, 98%) as anoff-white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 4.32 (t, 2H), 5.17 (t, 2H), 7.41 (s, 1H)

MS m/z 126 [M+H]⁺

Intermediate 30:(1R,2R)-2-(4-Bromobenzoyl)-N-(2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)cyclohexanecarboxamide

(1R,2R)-2-(4-Bromobenzoyl)cyclohexanecarboxylic acid (402 mg, 1.29 mmol)was added to a solution of 2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-aminehydrochloride (Intermediate 29, 209 mg, 1.29 mmol), HATU (738 mg, 1.94mmol) and DIPEA (0.90 mL, 5.17 mmol) in DMF (6 mL) at rt and thereaction mixture was stirred at for 16 h. The reaction mixture wasconcentrated in vacuo and diluted with EtOAc. The organic phase waswashed twice with brine, dried over Na₂SO₄, filtered and evaporated. Thecrude product was purified by preparative TLC (9% MeOH in DCM) to givethe title compound (200 mg, 37%).

MS m/z 418 [M+H]⁺

Intermediate 31: (5-Methyl-1H-pyrazol-3-yl)boronic acid hydrochloride

A solution of3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 2.95 g, 10.10 mmol) in MeOH (10 mL) was added dropwiseat 0° C. to HCl (3M in MeOH, 50 mL) and the reaction mixture was stirredat rt overnight. The reaction mixture was concentrated under vacuum andthe residue was washed with hexane (2×20 mL) to give the title compound(1.3 g) as a light brown solid.

MS m/z 127 [M+H]⁺

Intermediate 32: Ethyl5-(benzylsulfanyl)-1-methyl-1H-pyrazole-4-carboxylate

Dibenzyl disulfide (101.9 g, 413.57 mmol) was added in portions to asolution of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (10 g,59.11 mmol) in MeCN (400 mL) in an atmosphere of nitrogen and at rt.CuCl (293 mg, 7.14 mmol) was added in portions at rt to the reactionmixture and it was stirred at rt for 30 min. 3-Methyl-1-nitrobutane(41.5 g, 354.26 mmol) was added to the reaction mixture and theresulting solution was stirred at rt for 30 min and then at 60° C. for 1h. The reaction mixture was allowed to reach rt and the solids werefiltered off. The filtrate was concentrated under vacuum and the residuewas purified by silica gel column chromatography (EtOAc/petroleum ether,1:8) to give the title compound (11.6 g, 71%) as yellow oil.

MS m/z 277 [M+H]⁺

Intermediate 33: 5-(Benzylsulfanyl)-1-methyl-1H-pyrazole-4-carboxylicacid

Sodium hydroxide (5.04 g, 126.01 mmol) in water (30 mL) was addeddropwise at 0° C. to a solution of ethyl5-(benzylsulfanyl)-1-methyl-1H-pyrazole-4-carboxylate (Intermediate 32,11.6 g, 41.98 mmol) in MeOH (150 mL) and the reaction mixture wasstirred at rt for 15 h. The reaction mixture was concentrated undervacuum, the residue was dissolved in water and the aqueous phase waswashed EtOAc. The pH of the aqueous layer was adjusted to 5-6 with HCl(12 M, aq) and the solids formed were collected by filtration and driedunder vacuum to give the title compound (8.8 g, 84%) as a light yellowsolid.

MS m/z 249 [M+H]=249

Intermediate 34: tert-Butyl[5-(benzylsulfanyl)-1-methyl-1H-pyrazol-4-yl]carbamate

Boc₂O (30 g, 137.61 mmol) and Et₃N (10.7 g, 105.74 mmol) was added underan atmosphere of nitrogen to a solution of5-(benzylsulfanyl)-1-methyl-1H-pyrazole-4-carboxylic acid (Intermediate33, 8.8 g, 35.44 mmol) in tert-butanol (200 mL). Diphenyl phosphorylazide (19.5 g, 70.86 mmol) was added dropwise to the reaction mixtureand it was stirred at rt for 4 h and then at 88° C. for 15 h. Thereaction mixture was concentrated under vacuum. The residue wasdissolved in EtOAc and the organic phase was washed with NaHCO₃ (sat,aq) and brine, dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by silica gel column chromatography(EtOAc/petroleum ether, 1:6) to give the title compound (9.8 g, 87%) asyellow oil.

MS m/z 320 [M+H]⁺

Intermediate 35: 5-(Benzylsulfanyl)-1-methyl-1H-pyrazol-4-aminehydrochloride

HCl (g) was bubbled into a solution of tert-butyl[5-(benzylsulfanyl)-1-methyl-1H-pyrazol-4-yl]carbamate (Intermediate 34,9.8 g, 30.68 mmol) in MeOH (150 mL) at rt for 6 h. The reaction mixturewas concentrated under vacuum to give the title compound (7.5 g, 96%) asa light yellow solid.

MS m/z 220 [M+H]⁺

Intermediate 36:(1R,2R)—N-[5-(Benzylsulfanyl)-1-methyl-1H-pyrazol-4-yl]-2-(4-bromobenzoyl)cyclohexanecarboxamide

HATU (223 mg, 0.59 mmol) and5-(benzylsulfanyl)-1-methyl-1H-pyrazol-4-amine hydrochloride(Intermediate 35, 100 mg, 0.39 mmol) was added to a solution of(1R,2R)-2-[(4-bromophenyl)carbonyl]cyclohexane-1-carboxylic acid (122mg, 0.39 mmol) in DMF (10 mL). DIPEA (152 mg, 1.18 mmol) was addeddropwise to the reaction mixture and it was stirred at 20° C. for 15 h.Water was added to the reaction mixture and the aqueous phase wasextracted with EtOAc. The organic layer was washed with NaHCO₃ (sat, aq)and brine, dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by preparative TLC (EtOAc/Petroleum Ether, 1:5)and the crude product was purified by preparative HPLC on a Sunfire Cl18 column (150 mm) using a gradient of 55-100% MeCN in a H₂O/HCO₂H(99.5/0.5) buffer system as mobile phase to give the title compound (111mg, 55%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.23-1.12 (m, 1H), 1.52-1.37 (m, 3H),1.94-1.74 (m, 3H), 2.11-2.07 (m, 1H), 3.06-2.98 (t, 1H), 3.26 (s, 3H),3.74-3.66 (t, 1H), 3.89 (s, 2H), 7.06-7.03 (m, 2H), 7.25-7.21 (m, 3H),7.57 (s, 1H), 7.74-7.71 (d, 2H), 7.95-7.92 (d, 2H), 9.36 (s, 1H)

MS m/z 512 [M+H]⁺

Intermediate 37:(1R,2R)-2-(4-Bromobenzoyl)-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide

Step1—4-({[(1R,2R)-2-(4-Bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-5-sulfonylchloride

A mixture of(1R,2R)—N-[5-(benzylsulfanyl)-1-methyl-1H-pyrazol-4-yl]-2-(4-bromobenzoyl)cyclohexanecarboxamide(Intermediate 36, 7 g, 13.66 mmol) in AcOH (60 mL) was diluted withwater and cooled to −10° C.1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (4.05 g, 20.56 mmol)was added in one portion at −10° C. and the reaction mixture was stirredat −5° C. for 30 min. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione(1.35 g, 6.85 mmol) was added at 0° C. and the reaction mixture wasstirred for 30 min. 1,3-Dichloro-5,5-dimethytlimidazolidine-2,4-dione(1.35 g, 6.85 mmol) was added at about −5° C. and the reaction mixturewas stirred for 30 min. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione(1.35 g, 6.85 mmol) was added at about −5° C. and the reaction mixturewas stirred below 5° C. for 60 min. The reaction mixture was dilutedwith water and the aqueous phase was extracted with DCM. The organiclayer was washed with NaHCO₃ (8%, aq) until pH of the aqueous layer wasabout 6-7. The organic phase was concentrated under vacuum to give thesub-title compound (12 g, crude).

MS 488 m/z [M+H]=/490

Step2—(1R,2R)-2-(4-Bromobenzoyl)-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide

NH₃ (g) was bubbled into THF (300 mL) at −5° C. until the solvent wasnear saturation. A solution of4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-5-sulfonylchloride (19 g, 38.87 mmol) in THF (500 mL) was added dropwise withstirring at −5° C. and the reaction mixture was stirred at rt for 30min. The reaction mixture was concentrated under vacuum and the residuewas purified by silica gel column chromatography (EtOAc/petroleum ether,1:1) and then by silica gel medium pressure column chromatography usinga gradient of 20%-45% of MeCN in H₂O/HCO₂H (99.9/0.1) buffer system asmobile phase to give the title compound (12.0 g, 66%) as an off-whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.21-1.10 (m, 1H), 1.52-1.32 (m, 3H),1.83-1.72 (m, 2H), 2.08-1.90 (m, 2H), 2.90-2.83 (t, 1H), 3.71-3.65 (t,1H), 3.95 (s, 3H), 7.76-7.74 (d, 2H), 7.79 (s, 1H), 7.95-7.93 (d, 2H),8.03 (s, 2H), 8.82 (s, 1H)

MS 469 m/z [M+H]⁺

Intermediate 38:3-(Difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine

Step 1—Ethyl3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate

3,4-Dihydro-2H-pyran (1.3 g, 15.45 mmol) and 4-methylbenzenesulfonicacid (400 mg, 2.33 mmol) was added to a solution of ethyl3-(difluoromethyl)-1H-pyrazole-4-carboxylate (2.3 g, 12.10 mmol) in THF(50 mL) and the reaction mixture was stirred overnight at rt. Thereaction mixture was concentrated under vacuum and the residue wasdiluted with NaHCO₃ (aq, 50 mL) and then extracted with EtOAc. Theorganic phase was washed with brine, dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by silica gel columnchromatography (1.5→5% EtOAc in petroleum ether) to give the subtitlecompound (5 g, crude) as a brown oil.

Step2—3-(Difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylicacid

A solution of sodium hydroxide (220 mg, 5.50 mmol) in water (2 mL) wasadded to a solution of ethyl3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate(300 mg, 1.09 mmol) in EtOH (5 mL) and the reaction mixture was stirredat 60° C. for 5 h. The reaction mixture was concentrated under vacuumand the residue was diluted with water (3 mL) and the pH value of thesolution was adjusted to ˜3-4 with HCl (2M. aq). The precipitate wascollected by filtration and the solid was dried in an oven under vacuumto give the subtitle compound (0.15 g, 56%) as a white solid.

Step 3—Benzyl[3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]carbamate

DPPA (5.4 g, 19.62 mmol) and Et₃N (3.2 g, 31.62 mmol) was added to3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylicacid (4 g, 16.25 mmol) dissolved in a mixture of benzyl alcohol andtoluene (60 mL, 5:1) under a nitrogen atmosphere and the reactionmixture was heated to reflux for 2 h. The reaction mixture was extractedwith EtOAc and the combined organic layer was washed with brine, driedover Na₂SO₄, and concentrated under vacuum. The residue was purified bysilica gel column chromatography (5-33% EtOAc in petroleum ether) togive the subtitle compound (6 g, crude) as a yellow oil.

Step4—3-(Difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine

Pd/C (1 g) was added to a solution of benzyl[3-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]carbamate(4.2 g, 11.95 mmol) in EtOH (50 mL) and the reaction mixture was stirredat rt overnight under an atmosphere of H₂ (g). The solids were filteredto off and the filtrate was concentrated under vacuum. The residue waspurified by silica gel column chromatography (3-50% EtOAc in petroleumether) to give the title compound (2.4 g, 92%) as a red oil.

¹H-NMR (300 MHz, DMSO-d₆) δ 1.40-1.75 (m, 3H), 1.75-2.05 (m, 3H),3.50-3.70 (m, 1H), 4.30 (bs, 2H), 5.25 (d, 1H), 6.90 (t, 1H), 7.25 (s,1H).

MS m/z 218 [M+H]⁺

Intermediate 39:(1R,2R)-2-(4-Bromobenzoyl)-N-[5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanecarboxamide

HATU (2 g, 7.9 mmol) and DIPEA (2.2 g, 17 mmol) was added to a solutionof (1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (2 g, 6.45 mmol)in DMF (40 mL) and the reaction mixture was stirred at rt for 20 min.3-(Difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine(Intermediate 38, 1.68 g, 7.74 mmol) was added and the reaction mixturewas stirred at rt for 2 h. Ice-water (100 mL) was added to the reactionmixture and the precipitate was filtered and washed with water. Thecrude solid was dissolved in DCM (200 mL), dried over Na₂SO₄ andconcentrated under vacuum to give the title compound (1.5 g, 45%) as awhite solid.

MS m/z 532 [M+Na]⁺

Intermediate 40: tert-Butyl(5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate

Methyl1-(2-bromoethyl)-4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate(Intermediate 10, 5 g, 14.36 mmol) was added to a solution ofmethylamine (30 mL, 60.00 mmol) in THF (30 mL) at 25° C. and thereaction mixture was stirred at 70° C. for 15 h. The reaction mixturewas filtered through a pad of Celite and the filtrate was concentratedin vacuum. The crude product was purified by flash chromatography(0%-*1% MeOH in DCM) to give the title compound (3.20 g, 84%) as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.46 (s, 9H), 2.98 (s, 3H), 3.75 (t, 2H),4.30 (t, 2H), 7.75 (s, 1H), 8.01 (s, 1H)

MS m/z 267 [M+H]⁺

Intermediate 41:3-Amino-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onehydrochloride

HCl gas was bubbled into a solution of tert-butyl(5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate(Intermediate 40, 3.1 g, 11.64 mmol) in EtOAc (100 mL) and the reactionmixture was stirred at rt for 2 h. The precipitate was collected byfiltration, washed with EtOAc (50 mL) and dried under vacuum to give thetitle compound (2.2 g, 93%) as a white solid.

MS m/z 167 [M+H]⁺

Intermediate 42:(1R,2R)-2-(4-Bromobenzoyl)-N-(5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide

T3P (50% in EtOAc, 14.58 g, 22.92 mmol) was added to a mixture of(1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (1.78 g, 5.73mmol), 3-amino-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onehydrochloride (Intermediate 41, 1 g, 6.02 mmol) and Et₃N (3.20 mL, 22.92mmol) in butyl acetate (1 mL) at 25° C. and the reaction mixture wasstirred at 60° C. for 15 h. The solvent was removed under vacuum and thecrude product was purified by flash chromatography (0%→5% MeOH in DCM)to give the title compound (0.69 g, 26%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.55-1.10 (m, 4H), 1.83-1.70 (m, 2H),2.10-1.88 (m, 2H), 2.98 (t, 1H), 3.01 (s, 3H), 3.70 (t, 1H), 3.78 (t,2H), 4.30 (t, 2H), 7.75 (d, 2H), 7.81 (s, 1H), 7.92 (d, 2H), 9.20 (s,1H)

MS m/z 459 [M+H]⁺

Intermediate 43: (1R,2R and1S,2S)-2-(4-Bromobenzoyl)-N-(5-cyano-1-methyl-1H-pyrazol-4-yl)cyclohexanecarboxamide

(1R,2R and 1S,2S)-2-(4-Bromobenzoyl)cyclohexanecarboxylic acid (2.0 g,6.4 mol) was added to a mixture of4-amino-1-methyl-1H-pyrazole-5-carbonitrile (2.0 g, 6.4 mol), T3P (50%in EtOAc, 2.0 g, 9.4 mol) and DMAP (1.8 g, 1.5 mol) in DCE (10 mL) andthe reaction mixture was stirred in a microwave reactor at 100° C. for 1h. The reaction mixture was diluted with DCM and the organic layer waswashed with brine, dried and concentrated in vacuum. The residue waspurified by silica gel chromatography (17% EtOAc in petroleum ether)give the title compound (0.4 g, 17%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.39-1.49 (m, 3H), 1.69-1.76 (m, 1H),1.85-1.94 (m, 2H), 2.04-2.10 (m, 2H), 2.83-2.90 (m, 1H), 3.64-3.71 (m,1H), 3.95 (s, 3H), 7.56 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 7.89 (s, 2H)

MS m/z 415.1 [M+H]⁺

Intermediate 44:1-Ethyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide

T3P (50% in EtOAc, 293 μL, 0.98 mmol) and Et₃N (422 μL, 3.03 mmol) wereadded to a solution of(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxylicacid (Intermediate 8, 300 mg, 0.76 mmol) and4-amino-1-ethyl-1H-pyrazole-5-carboxamide (152 mg, 0.98 mmol) in EtOAc(2.3 mL) and the reaction mixture was heated in a sealed vessel at 80°C. for 1.5 h. 4-Amino-1-ethyl-1H-pyrazole-5-carboxamide (152 mg, 0.98mmol), Et₃N (422 μL, 3.03 mmol) and T3P (50% in EtOAc, 293 μL, 0.98mmol) were added to the reaction mixture and it was heated at 80° C. for1 h and then stirred at rt over night. The reaction mixture was purifiedby flash chromatography using EtOAc as mobile phase to give the titlecompound (150 mg, 37%).

MS m/z 531.3 [M−H]⁻

Intermediate 45: Methyl4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}-amino)-1-methyl-1H-pyrazole-5-carboxylate

Et₃N (1.8 mL, 12.99 mmol) and T3P (50% in EtOAc, 4 mL, 6.72 mmol) wereadded to a solution of (1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylicacid (1 g, 3.21 mmol) and methyl4-amino-1-methyl-1H-pyrazole-5-carboxylate (1 g, 6.45 mmol) in EtOAc (15mL) and the reaction mixture was stirred at rt for 1 h and then heatedat 73-77° C. for 2 h. The reaction mixture was diluted with EtOAc (100mL) and the organic phase was washed with NaHCO₃ (sat, aq), dried usinga phase separator and concentrated in vacuum. The residue was purifiedby flash chromatography (30%→100% EtOAc in heptane) to give the titlecompound (1.22 g, 85%) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.25-1.40 (m, 1H), 1.43 (dqt, 2H), 1.71 (qd,1H), 1.84-1.95 (m, 2H), 1.99-2.08 (m, 1H), 2.11 (dd, 1H), 2.92 (ddd,1H), 3.67 (ddd, 1H), 4.03 (s, 3H), 4.07 (s, 3H), 7.56-7.63 (m, 2H),7.8-7.87 (m, 2H), 8.12 (s, 1H), 8.88 (s, 1H).

MS m/z 448 [M+H]⁺

Intermediate 46: Methyl1-methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxylate

A solution of K₂CO₃ (1.44 g, 10.44 mmol) in water (15 mL) followed byPd(dtbpf)Cl₂ (168 mg, 0.26 mmol) was added to a solution of methyl4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxylate(Intermediate 45, 1.17 g, 2.61 mmol) and3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 1.91 g, 6.52 mmol) in dioxane (15 mL) under anatmosphere of nitrogen and the reaction mixture was heated to 80° C. for1 h. The reaction mixture was diluted with EtOAc (200 mL) and theorganic phase was washed with brine (sat.), dried using a phaseseparator and concentrated in vacuum. The residue was purified by flashchromatography (20%→100% of EtOAc in heptane) to give the title compound(0.85 g, 61%).

¹H NMR (500 MHz, CDCl₃) δ 1.23-1.6 (m, 6H), 1.69 (tdd, 3H), 1.8-1.93 (m,2H), 2.08 (dd, 2H), 2.39 (d, 1H), 2.52 (tdt, 1H), 2.87-3.01 (m, 1H),3.55 (qd, 1H), 3.72 (ddd, 1H), 3.98 (s, 3H), 3.99-4.04 (m, 3H), 5.06(dt, 1H), 6.12 (s, 1H), 7.54 (d, 2H), 8.02 (d, 2H), 8.09 (d, 1H), 8.88(s, 1H).

MS m/z 534.2 [M+H]⁺

Intermediate 47:N,1-Dimethyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide

Step1—1-Methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxylicacid

LiOH (1M in H₂O, 3 mL, 3.00 mmol) was added dropwise over 10 min to asolution of methyl1-methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxylate(Intermediate 46, 0.78 g, 1.46 mmol) in THF (3 mL) and MeOH (3 mL) andthe reaction mixture was stirred at rt for 50 min. The reaction mixturewas diluted with EtOAc and stirred at rt for 5 min and then concentratedin vacuum to give the title compound (0.75 g, 99%).

MS m/z 519.0 [M+H]⁺

Step2—N,1-Dimethyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide

T3P (50% in EtOAc, 344 μL, 0.58 mmol), methylamine hydrochloride (22 μL,0.38 mmol) and DIPEA (134 μL, 0.77 mmol) were added to a suspension of1-methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]-carbonyl}-amino)-1H-pyrazole-5-carboxylicacid (0.1 g, 0.19 mmol) in EtOAc (0.8 mL) and the reaction mixture wasstirred at rt for 1 h and then heated in a microwave reactor at 60° C.for 1 h. Methylamine hydrochloride (22 μL, 0.38 mmol) and DIPEA (134 μL,0.77 mmol) was added to the reaction mixture and it was heated in amicrowave reactor at 60° C. for 1 h. The reaction mixture was dilutedwith EtOAc and NaHCO₃ (sat., aq) and the organic phase was dried using aphase separator and concentrated in vacuum. The crude product waspurified by flash chromatography (100% EtOAc) to give the title compound(0.067 g, 65%).

MS m/z 531.4 [M−H]⁻

Intermediate 48:5-Methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-3-carboxamide

DIPEA (352 μL, 2.02 mmol) and HATU (230 mg, 0.61 mmol) were added to asolution of(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}-cyclohexanecarboxylicacid (Intermediate 8, 200 mg, 0.50 mmol) in DMF (4 mL) and the reactionmixture was stirred at rt for 5 min.4-Amino-5-methyl-1H-pyrazole-3-carboxamide (106 mg, 0.76 mmol) was addedto the reaction mixture and it was stirred at rt for 15 h. The reactionmixture was diluted with EtOAc and the organic phase was washed withNaHCO₃ (sat., aq), NH₄Cl (sat., aq) and brine. The organic phase wasdried using a phase separator and concentrated under vacuum. The residuewas purified by flash chromatography (0%→10% of EtOH in EtOAc), thecompound containing fractions were collected, concentrated in vacuum,and the residue was dissolved in DCM and concentrated in vacuum to givethe title compound (190 mg, 73%) as a beige solid.

MS m/z 417.1 [M−H]⁻

Intermediate 49: 14-({[(1R,2R)-2-{4-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide

A solution of (1R,2R)-2-{4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5yl]benzoyl}cyclohexanecarboxylic acid (Intermediate 69, 300 mg, 0.78mmol) in DMF (3.0 mL) was added to a solution of4-amino-1H-pyrazole-5-carboxamide hydrochloride (255 mg, 1.57 mmol) andEt₃N (381 μL, 2.75 mmol) in EtOAc (3 mL). T3P (50% in EtOAc, 0.70 mL,1.18 mmol) was added and the reaction mixture was heated at 80° C. for 1h and then stirred at rt over night. The reaction mixture was dilutedwith NaHCO₃ (8%, aq) and EtOAc. The aqueous layer was extracted withEtOac and the combined organic layer was dried using a phase separatorand concentrated under vacuum. The residue was purified by preparativeHPLC on an XBridge C18 column (10 μm 250×19 ID mm) using a gradient of10-80% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system, to give thetitle compound (97 mg 25%).

MS m/z 489.3 [M−H]⁻

Intermediate 50:(1R,2R)—N-(4-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-{4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxamide

A solution of1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.511 g, 1.84 mmol) in dioxane (5 mL) was added to(1R,2R)-2-(4-bromobenzoyl)-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(Intermediate 13, 0,545 g, 1.22 mmol). A solution of K₂CO₃ (0.677 g,4.90 mmol) in water (5 mL) was added to the reaction mixture and it wasevacuated and purged with nitrogen three times. The reaction mixture washeated to 50° C. and Pd(dtbpf)Cl₂ (0.040 g, 0.06 mmol) was added and thereaction mixture was heated at 50° C. for 10 min. The reaction mixturewas diluted with EtOAc (5 ml) and the organic phase was washed withwater. The aqueous phase was extracted with EtOAc and then the combinedorganic phase was washed with brine, dried using a phase separator andconcentrated in vacuum. The residue was purified by flash chromatography(EtOAc) to give the title compound (0.460 g, 72.8%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 1.31-1.53 (m, 3H), 1.63-1.99 (m, 6H),2.06-2.25 (m, 3H), 2.47-2.71 (m, 1H), 2.93-3.08 (m, 1H), 3.63 (q, 1H),3.80 (d, 3H), 4.13 (q, 2H), 4.31 (t, 2H), 5.21 (d, 1H), 5.91 (s, 1H),6.33-6.46 (m, 1H), 7.62 (dd, 3H), 8.10 (d, 2H), 8.16 (s, 1H), 8.84 (s,1H).

MS m/z 515.6 [M−H]⁻

Intermediate 51: Ethyl1-methyl-5-(methylsulfamoyl)-1H-pyrazole-4-carboxylate

A solution of ethyl5-(chlorosulfonyl)-1-methyl-1H-pyrazole-4-carboxylate (10.0 g, 39.6mmol) in THF (20 mL) was added dropwise with stirring at 0-2° C. during20 min to a mixture of methylamine (33% aq, 20.4 g, 217 mmol) and K₂CO₃(5.4 g, 38.79 mmol). The reaction mixture was stirred at 0-2° C. in awater/ice bath for 40 min. The reaction mixture was concentrated undervacuum. The residue was extracted with tert-butyl methyl ether and theorganic layer was dried over Na₂SO₄ and concentrated in vacuum to givethe title compound (9.5 g, 97%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 1.35 (t, 3H), 2.67 (d, 3H), 4.20 (s, 3H), 4.32(q, 2H), 6.85-6.74 (m, 1H), 7.92 (s, 1H)

Intermediate 52: 1-Methyl-5-(methylsulfamoyl)-1H-pyrazole-4-carboxylicacid

A solution of NaOH (3.9 g, 97.5 mmol) in water (20 mL) was added to asolution of ethyl 1-methyl-5-(methylsulfamoyl)-1H-pyrazole-4-carboxylate(Intermediate 51, 9.5 g, 38.4 mmol) in MeOH (10 mL) and the reactionmixture was stirred at 40° C. for 1 h. The reaction mixture wasconcentrated under vacuum and the resulting mixture was washed twicewith tert-butyl methyl ether. The pH value of the solution was adjustedto 2-3 with HCl (6 M, aq).

The solids were collected by filtration to give the title compound (5.7g, 68%) as an off-white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 2.53 (s, 3H), 4.08 (s, 3H), 7.50 (s, 1H),7.94 (s, 1H), 13.20 (s, 1H).

Intermediate 53:2,7-Dimethyl-4,7-dihydropyrazolo[4,3-e][1,2,4]thiadiazin-3(2H)-one1,1-dioxide

DIPEA (3.67 g, 28.40 mmol) was added to a solution of1-methyl-5-(methylsulfamoyl)-1H-pyrazole-4-carboxylic acid (Intermediate52, 4.8 g, 21.90 mmol) in toluene (25 mL). DPPA (7.83 g, 28.45 mmol) wasadded dropwise to the reaction mixture with stirring at 80-85° C. in 20min and the reaction mixture was stirred at 85° C. for 3 h. The reactionmixture was concentrated under vacuum and the residue was purified bysilica gel column chromatography (50% EtOAc in Petroleum ether) to givethe title compound (3.2 g, 68%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃,) δ 3.40 (s, 3H), 4.12 (s, 3H), 7.34 (s, 1H),9.28 (s, 1H).

Intermediate 54: 4-Amino-N,1-dimethyl-1H-pyrazole-5-sulfonamidehydrochloride

HCl (6M, aq, 43 mL) was added to a solution of2,7-dimethyl-4,7-dihydropyrazolo[4,3-e][1,2,4]thiadiazin-3(2H)-one1,1-dioxide (Intermediate 53, 3.5 g, 16.19 mmol) in 1,4-dioxane (2 mL)and the reaction mixture was stirred at 95° C. for 3 days. The reactionmixture was allowed to reach rt and the pH value of the solution wasadjusted to 9-10 with K₂CO₃ (sat., aq). The resulting solution wasextracted with EtOAc and the organic layer was dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by silica gel columnchromatography (50% EtOAc in Petroleum ether) to give the title compound(2.8 g, 91%) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.43 (s, 3H), 3.81 (s, 3H), 4.66 (s, 2H),7.05 (s, 1H), 7.67 (s, 1H)

MS m/z 191 [M+H]⁺

Intermediate 55:(1R,2R)-2-(4-Bromobenzoyl)-N-[1-methyl-5-(methylsulfamoyl)-1H-pyrazol-4-yl]cyclohexanecarboxamide

T3P (50% in EtOAc, 2.73 g, 8.58 mmol) and Et₃N (870 mg, 8.60 mmol) wereadded to a solution of(1R,2R)-2-[(4-bromophenyl)carbonyl]cyclohexane-1-carboxylic acid (533mg, 1.71 mmol) and 4-amino-N,1-dimethyl-1H-pyrazole-5-sulfonamidehydrochloride (Intermediate 54, 327 mg, 1.72 mmol) in EtOAc (10 mL) andthe reaction mixture was stirred at 70° C. for 4 h. The reaction mixturewas extracted with EtOAc and the combined organic layer was washed withsodium hydroxide (2N, aq), brine, dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by silica gel columnchromatography (17%→33% EtOAc in Petroleum ether) to give the titlecompound (350 mg, 42%) as a white solid.

MS m/z 483 [M+H]⁺

Intermediate 56:(1R,2R)—N-[1-Methyl-5-(methylsulfamoyl)-1H-pyrazol-4-yl]-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexane-carboxamide

Pd(dppf)Cl₂*DCM (33.8 mg, 0.05 mmol) and K₂CO₃ (171 mg, 1.24 mmol) wasadded to a mixture of(1R,2R)-2-(4-bromobenzoyl)-N-[1-methyl-5-(methylsulfamoyl)-1H-pyrazol-4-yl]cyclohexanecarboxamide(Intermediate 55, 200 mg, 0.41 mmol) and3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole(Intermediate 3, 218 mg, 1.04 mmol) in dioxane/H₂O (1:1, 5 mL) and thereaction mixture was stirred at 50° C. for 30 min. The reaction mixturewas extracted with EtOAc and the combined organic layer was washed withbrine, dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by silica gel column chromatography (11%→50% EtOAc in Petroleumether) to give the title compound (240 mg, 97%) as a red solid.

MS m/z 569 [M+H]⁺

Intermediate 57: Ethyl5-(dimethylsulfamoyl)-1-methyl-1H-pyrazole-4-carboxylate

Ethyl 5-(chlorosulfonyl)-1-methyl-1H-pyrazole-4-carboxylate (10 g, 39.58mmol) was added to a solution of dimethylamine (2 M in THF, 45 mL, 89.45mmol) in THF (30 mL) and the reaction mixture was stirred at rt for 10min. The reaction mixture was diluted with EtOAc (100 mL) and theorganic phase was washed with water, brine and concentrated in vacuum togive the title compound (8 g, 77%) as red oil.

MS m/z 262 [M+H]⁺

Intermediate 58: 5-(Dimethylsulfamoyl)-1-methyl-1H-pyrazole-4-carboxylicacid

A solution of NaOH (3.8 g, 95.01 mmol) in water (50 mL) was added to asolution of ethyl5-(dimethylsulfamoyl)-1-methyl-1H-pyrazole-4-carboxylate (Intermediate57, 5 g, 19.14 mmol) in MeOH (100 mL) and the reaction mixture wasstirred at 40° C. for 2 h. The solvent was removed in vacuo and the pHvalue of the solution was adjusted to 2-3 with HCl (1M, aq). The solidwas collected by filtration and the filtrate was extracted with of EtOAc(2×20 mL). The organic layer was concentrated and the solids werecombined and dried in vacuum to give the title compound (3.8 g, 85%) asa red solid.

MS m/z 234 [M+H]⁺

Intermediate 59: tert-Butyl[5-(dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-yl]carbamate

DPPA (6.1 g, 22.3 mmol) and DIPEA (3.8 g, 29.40 mmol) was added to asolution of 5-(dimethylsulfamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid(Intermediate 58, 3.7 g, 15.86 mmol) in tert-BuOH (50 mL) and thereaction mixture was stirred at 85° C. for 15 h. The solvent was removedunder vacuum and the residue was dissolved in EtOAc. The organic phasewas washed with water, concentrated in vacuum and the residue waspurified by silica gel column chromatography (33% EtOAc in Petroleumether) to give the title compound (2.5 g, 52%) as a yellow solid.

MS m/z 305 [M+H]⁺

Intermediate 60: 4-Amino-N,N,1-trimethyl-1H-pyrazole-5-sulfonamidehydrochloride

A solution of tert-butyl[5-(dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-yl]carbamate (Intermediate59, 500 mg, 1.64 mmol) in EtOAc (20 mL), was treated with HCl (g) andthe reaction mixture was stirred at rt for 1 h. The solvent was removedunder vacuum to give the title compound (390 mg, 99%) as a pink solid.

MS m/z 205 [M+H]⁺

Intermediate 61:(1R,2R)-2-(4-Bromobenzoyl)-N-[5-(dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-yl]cyclohexanecarboxamide

HATU (844 mg, 2.22 mmol) and DIPEA (573 mg, 4.43 mmol) was added to asolution of (1R,2R)-2-[(4-bromophenyl)carbonyl]cyclohexane-1-carboxylicacid (358 mg, 1.15 mmol) and 4-amino-N,N,1-trimethyl-1H-pyrazole-5-sulfonamide hydrochloride (Intermediate 60,280 mg, 1.16 mmol) in DMF (8 mL) the reaction mixture was stirred at rtfor 4 h. The solvent was removed under vacuum and the residue waspurified by preparative TLC (4.7% MeOH in DCM) to give the titlecompound (130 mg, 23%) as a yellow solid.

MS m/z 497 [M+H]⁺

Intermediate 62: Ethyl 4-amino-3-methyl-1H-pyrazole-5-carboxylate

Pd—C (500 mg, 4.70 mmol) was added to a solution of ethyl3-methyl-4-nitro-1H-pyrazole-5-carboxylate (4.75 g, 23.85 mmol) in MeOH(50 mL) and the reaction mixture was stirred under an atmosphere ofhydrogen at rt for 20 h. The solid was filtered off and the filtrate wasconcentrated under vacuum to give the title compound (3.8 g, 94%).

MS m/z 170 [M+H]⁺

Intermediate 63: Ethyl4-[(tert-butoxycarbonyl)amino]-3-methyl-1H-pyrazole-5-carboxylate

Boc₂O (2.13 mL, 9.16 mmol) was added to a solution of ethyl4-amino-3-methyl-1H-pyrazole-5-carboxylate (Intermediate 62, 1.5 g, 8.87mmol) and pyridine (1.42 mL, 17.57 mmol) in MeOH (40 mL) and thereaction mixture was stirred at rt for 4 h. The reaction mixture wasconcentrated under vacuum to give the title compound (2.1 g, 88%)

MS m/z 270 [M+H]⁺

Intermediate 64: Ethyl1-(2-bromoethyl)-4-[(tert-butoxycarbonyl)amino]-3-methyl-1H-pyrazole-5-carboxylate

1,2-Dibromoethane (1.6 g, 8.52 mmol) was added to a solution of ethyl4-[(tert-butoxycarbonyl)amino]-3-methyl-1H-pyrazole-5-carboxylate(Intermediate 63, 2.1 g, 7.80 mmol) and K₂CO₃ (2.1 g, 15.19 mmol) in DMF(80 mL) and the reaction mixture was stirred at rt for 3 h. The solidswere filtered off and the filtrate was concentrated under vacuum. Theresidue was purified by silica gel column chromatography (20% EtOAc inPetroleum ether) to give the title compound (1 g, 34%).

¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (t, 3H), 1.43 (s, 9H), 2.08 (s, 3H),3.78 (t, 2H), 4.25 (q, 2H), 4.73 (t, 2H)

MS m/z 376 [M+H]+

Intermediate 65: tert-Butyl(2-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate

Ethyl1-(2-bromoethyl)-4-[(tert-butoxycarbonyl)amino]-3-methyl-1H-pyrazole-5-carboxylate(Intermediate 64, 1 g, 2.66 mmol) was suspended in MeCN (9 mL) andammonia (25%, aq, 3 mL, 77.04 mmol) in a pressure reactor and thereactor was heated in an oil bath at 60° C. for 16 h. The reactionmixture was concentrated under vacuum and the resulting mixture waswashed with a mixture of EtOAc/Petroleum ether (1:2). The solids werecollected by filtration and dried under vacuum to give the titlecompound (650 mg, 92%) as an off-white solid.

MS m/z 267 [M+H]⁺

Intermediate 66:3-Amino-2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onehydrochloride

HCl (gas) was bubbled into a solution of tert-butyl(2-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate(Intermediate 65, 650 mg, 2.44 mmol) in MeOH (15 mL) at rt for 20 min.The resulting mixture was concentrated under vacuum to give the titlecompound (460 mg, 93%) as a white solid.

¹H NMR (300 MHz DMSO-d₆) δ 2.23 (s, 3H), 3.63-3.58 (m, 2H), 4.23-4.19(t, 2H), 7.49-7.15 (m, 2H), 8.46 (s, 1H), 9.78-8.78 (br, 1H)

MS m/z 167 [M+H]⁺

Intermediate 67:(1R,2R)-2-(4-Bromobenzoyl)-N-(2-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide

3-Amino-2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onehydrochloride (Intermediate 66, 460 mg, 2.27 mmol) and DIPEA (1.18 g,9.13 mmol) were added to a mixture of(1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (708 mg, 2.28 mmol)and HATU (1.73 g, 4.55 mmol) in DMF (20 mL) and the reaction mixture washeated at 50° C. for 16 h. The reaction mixture was concentrated undervacuum and the residue was dissolved in EtOAc. The reaction mixture wasdiluted with EtOAc and the organic phase was washed with NaHCO₃ (aq) andbrine, dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel column chromatography (4.7% MeOH inDCM) to give the title compound (630 mg, 60%) as a light yellow solid.

MS m/z 441 [M+H]⁺

Intermediate 68:(1R,2R)—N-[5-(Difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

1H-Pyrazol-3-ylboronic acid (169 mg, 1.51 mmol), K₂CO₃ (568 mg, 4.11mmol) and Pd(dppf)Cl₂*DCM (112 mg, 0.14 mmol) were added to a solutionof(1R,2R)-2-(4-bromobenzoyl)-N-[5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanecarboxamide(Intermediate 39, 700 mg, 1.37 mmol) in a mixture of dioxane and water(4:1, 15 mL) under an atmosphere of nitrogen and the reaction mixturewas stirred at 50° C. for 2 h. The reaction mixture was diluted withEtOAc and the organic phase was washed with water, brine (sat.), driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bysilica gel column chromatography (33% EtOAc in Petroleum ether) to givethe title compound (520 mg, 76%) as brown oil.

MS m/z 498 [M+H]⁺

Intermediate 69:(1R,2R)-2-{4-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5yl]benzoyl}cyclohexanecarboxylicacid

K₂CO₃ (3.94 g, 28.5 mmol) and Pd(dtbpf)Cl₂ (232 mg, 0.36 mmol) wereadded to a solution of (1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylicacid (2.22 g, 7.12 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.97 g, 10.68 mmol) in 1,4-dioxane (40 mL) and water (20 mL). Thereaction mixture was evacuated and purged with nitrogen three times andthen heated at 80° C. for 1 h. The reaction mixture was diluted withEtOAc washed with KHSO₄ (1M, aq). The aqueous phase was extracted withEtOAc (×2) and the combined organic phase was dried using phaseseparator and concentrated under reduced pressure. The crude product waspurified by preparative HPLC on a Kromasil C8 column (10 m 250×50 ID mm)using a gradient of 30-90% MeCN in H₂O/MeCN/AcOH (95/5/0.2) buffersystem to give the title product (2.72 g, 100%) as a brown solid.

¹H NMR (500 MHz, CDCl₃) δ 1.23-1.34 (m, 1H), 1.36-1.47 (m, 2H),1.47-1.66 (m, 3H), 1.71-1.83 (m, 1H), 1.83-1.94 (m, 3H), 2.05-2.12 (m,2H), 2.24-2.31 (m, 1H), 2.54-2.65 (m, 1H), 2.95-3.02 (m, 1H), 3.54-3.68(m, 2H), 4.12-4.18 (m, 1H), 5.22 (dd, 1H), 6.38-6.41 (m, 1H), 7.61-7.67(m, 3H), 8.03-8.09 (m, 2H). MS m/z 381.3 [M−H]⁻

Intermediate 70: Ethyl 4-(4-bromo-2-chlorophenyl)-4-hydroxybut-2-ynoate

n-Butyllithium (1.6M in hexane, 44 mL, 70.4 mmol) was added to asolution of DIPEA (10 mL, 69.2 mmol) in THF (100 mL) under an atmosphereof nitrogen at −78° C. for 30 min. Ethyl prop-2-ynoate (6.5 mL, 64.3mmol) was added dropwise to the reaction mixture followed by theaddition of a solution of 4-bromo-2-chlorobenzaldehyde (14.11 g, 64.3mmol) in THF (25 mL) and the reaction mixture was stirred at −78° C.over night. AcOH (12 mL) in THF (50 mL) was added to the reactionmixture and it was then poured into water (800 mL). The reaction mixturewas extracted four times with DCM. The combined organic phase was driedover MgSO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (20%→50% EtOAc in heptane) to give thetitle compound (11.0 g, 54%).

¹H NMR (400 MHz, CDCl₃) δ 1.31 (t, 3H), 2.70 (d, 1H), 4.24 (q, 2H), 5.86(d, 1H), 7.47 (dd, 1H), 7.55-7.61 (m, 2H)

MS m/z 316.9 [M−H]⁻

Intermediate 71: Ethyl (2E)-4-(4-bromo-2-chlorophenyl)-4-oxobut-2-enoate

Et₃N (5 mL, 36.07 mmol) was added to a solution of ethyl4-(4-bromo-2-chlorophenyl)-4-hydroxybut-2-ynoate (Intermediate 70, 11 g,34.6 mmol) in 1,4-dioxane (50 mL) and the reaction mixture was stirredat 60° C. for 4 h. The reaction mixture was concentrated in vacuo, theresidue was redissolved in EtOAc and the organic phase was washed withHCl (1M, aq). The crude product was purified by flash chromatography(0%→25% EtOAc in heptane) to give the title compound (7.8 g, 71%).

¹H NMR (400 MHz, CDCl₃) δ 1.33 (t, 3H), 4.28 (q, 2H), 6.66 (d, 1H), 7.38(d, 1H), 7.46-7.54 (m, 2H), 7.64 (d, 1H).

Intermediate 72: Ethyl (1R,6R and1S,6S)-6-(4-bromo-2-chlorobenzoyl)cyclohex-3-ene-1-carboxylate

Buta-1,3-diene (14 mL, 165.65 mmol), condensed at −78° C., was added toa mixture of ethyl (2E)-4-(4-bromo-2-chlorophenyl)-4-oxobut-2-enoate(Intermediate 71, 4.04 g, 12.72 mmol) and hydroquinone (0.011 g, 0.10mmol) in toluene (15 mL) at −78° C. and the reaction vessel was sealedand stirred at rt for 1 h and then heated at 210° C. for 15 h. The crudeproduct was purified by flash chromatography (5%→25% EtOAc in heptane)to give the title compound (4.47 g, 95%).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (t, 3H), 2.08 (dddd, 1H), 2.21 (dddd,1H), 2.26-2.39 (m, 1H), 2.52 (dd, 1H), 3.02 (td, 1H), 3.63 (td, 1H),4.12 (qd, 2H), 5.63-5.77 (m, 2H), 7.47 (dd, 1H), 7.56 (d, 1H), 7.60 (d,1H).

Intermediate 73: 4-({[(1R,6R and1S,6S)-6-(4-Bromo-2-chlorobenzoyl)cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide

Step 1 (1R,6R and1S,6S)-6-(4-Bromo-2-chlorobenzoyl)cyclohex-3-ene-1-carboxylic acid

Water (20 mL) and LiOH (1.0 g, 41.76 mmol) was added to a solution ofethyl (1R,6R and1S,6S)-6-(4-bromo-2-chlorobenzoyl)cyclohex-3-ene-1-carboxylate(Intermediate 72, 4.43 g, 11.92 mmol) in THF (40 mL) and MeOH (40 mL)and the reaction mixture was stirred at 60° C. for 2 h. The reactionmixture was concentrated in vacuo and the residue was acidified by theaddition of HCl (2M, aq). The water phase was extracted three times withdiethyl ether and the combined organic phase was dried over MgSO₄,filtered and concentrated in vacuo to give the subtitle compound (3.69g, 90%).

Step 2: 4-({[(1R,6R and1S,6S)-6-(4-Bromo-2-chlorobenzoyl)cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide

T3P (50% in EtOAc, 640 mg, 2.01 mmol) and DMAP (300 mg, 2.46 mmol) wereadded to a solution of (1R,6R and1S,6S)-6-(4-bromo-2-chlorobenzoyl)cyclohex-3-ene-1-carboxylic acid(Intermediate 73 Step 1, 571 mg, 1.16 mmol) and4-amino-1-methyl-1H-pyrazole-5-carboxamide (280 mg, 2.0 mmol) in THF (12mL) and DCM (1 mL) and the reaction mixture was stirred at rt for 15 h.Water (5 mL) was added and the reaction mixture was concentrated underreduced pressure. The residue was diluted with water and the water phasewas extracted with EtOAc. The organic phase was washed with brine andconcentrated under reduced pressure. The residue was dissolved in DCM,dried using a phase separator and the crude product was purified byflash chromatography (20% acetone in EtOAc) to give the title compound(470 mg, 87%).

¹H NMR (400 MHz, CDCl₃) δ 2.04-2.15 (m, 1H), 2.31-2.56 (m, 3H), 2.98(td, 1H), 3.74 (td, 1H), 4.09 (s, 3H), 5.76 (d, 2H), 6.17 (s, 2H),7.44-7.49 (m, 1H), 7.54 (d, 1H), 7.61 (d, 1H), 7.70 (s, 1H), 8.09 (s,1H).

MS m/z 465.1 [M−H]⁻

Intermediate 74: 4-[({(1R,6R and1S,6S)-6-[2-Chloro-4-(1H-pyrazol-5-yl)benzoyl]-cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

4-({[(1R,6R and 1S,6S)-6-(4-Bromo-2-chlorobenzoyl)cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 73, 230 mg, 0.49 mmol), 1H-pyrazol-5-ylboronic acid (112mg, 1 mmol), K₂CO₃ (140 mg, 1.01 mmol) and Pd(dtbpf)Cl₂ (20 mg, 0.03mmol) were suspended in a mixture of dioxane (8 ml) and water (2 mL).The reaction vessel was evacuated and purged with nitrogen (g) and thenheated at 90° C. for 1.5 h. The reaction mixture was concentrated invacuo and the residue was diluted with EtOH (50 mL). NaHCO₃ (sat., aq)was added until pH 8 and the reaction mixture was concentrated todryness under reduced pressure. The crude product was purified bypreparative HPLC on a XBridge C18 column (10 μm, 250×19 ID mm) using agradient of 5-95% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system asmobile phase to give the title compound (28 mg, 13%).

MS m/z 451.1 [M−H]⁻

Intermediate 75: 4-[({(1R,6R and1S,2S)-6-[2-Chloro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

Step 1: 4-({[(1R,6R and1S,6S)-6-{2-Chloro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzyl}cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide

4-({[(1R,6R and 1S,6S)-6-(4-Bromo-2-chlorobenzoyl)cyclohex-3-en-1-yl]carbonyl}-amino)-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 73, 230 mg, 0.49 mmol),3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 300 mg, 1.03 mmol), K₂CO₃ (150 mg, 1.09 mmol) andPd(dtbpf)Cl₂ (20 mg, 0.03 mmol) were suspended in a mixture of dioxane(8 mL) and water (2 mL). The reaction vessel was evacuated and purgedwith nitrogen (g) and heated at 90° C. for 30 min. The reaction mixturewas used directly after cooling in the next step.

Step 2: 4-[({(1R,6R and1S,2S)-6-[2-Chloro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

HCl (4 M in dioxane, 0.5 mL, 2.00 mmol) was added to the reactionmixture from Intermediate 75 Step 1 and the reaction mixture was stirredat rt for 10 min. The reaction mixture were concentrated at reducedpressure, NaHCO₃ (sat., aq) was added to the residue until pH 8 and thewater phase was extracted twice with DCM. The combined organic phase wasdried using a phase separator and concentrated to dryness at reducedpressure. The crude product was purified by flash chromatography (EtOAc)and then by preparative HPLC on a XBridge C18 column (10 μm 250×19 IDmm) using a gradient of 5-95% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffersystem as mobile phase to give the title compound (100 mg, 59%).

MS m/z 465.2 [M−H]⁻

Intermediate 76: Methyl 4-(4-bromo-2-fluorophenyl)-4-hydroxybut-2-ynoate

n-Butyllithium (1.6 M in Hexane, 45 mL, 72.0 mmol) was added to asolution of DIPEA (10 mL, 69.2 mmol) in THF (100 mL) under an atmosphereof nitrogen at −78° C. and the reaction mixture was stirred at −78° C.for 30 min. Methyl prop-2-ynoate (5.7 mL, 64.5 mmol) was added dropwise,then a solution of 4-bromo-2-fluorobenzaldehyde (13.1 g, 64.5 mmol) inTHF (20 mL) was added and the reaction mixture was stirred at −78° C.over night. AcOH (10 mL) was added to the reaction mixture and it waspoured into water. The reaction mixture was extracted with DCM and thecombined organic phase was dried over MgSO₄, filtered and concentratedin vacuo. The crude product was purified flash chromatography (20%→50%EtOAc in heptane) to give the title compound (12.9 g, 70%).

¹H NMR (400 MHz, CDCl₃) δ 2.62 (s, 1H), 3.79 (s, 3H), 5.78 (s, 1H), 7.29(dd, 1H), 7.35 (dd, 1H), 7.49 (t, 1H).

MS m/z 285.0 [M−H]⁻

Intermediate 77: Methyl(2E)-4-(4-bromo-2-fluorophenyl)-4-oxobut-2-enoate

Et₃N (12.5 mL, 90.2 mmol) was added to a solution of methyl4-(4-bromo-2-fluorophenyl)-4-hydroxybut-2-ynoate (Intermediate 76, 12.9g, 44.9 mmol) in 1,4-dioxane (40 mL) and the reaction mixture wasstirred at rt over night and then heated at 60° C. for 30 min. Thereaction mixture was concentrated in vacuo and the crude product waspurified by flash chromatography (0%→25% EtOAc in heptane) to give thetitle compound (9.7 g, 75%).

¹H NMR (400 MHz, CDCl₃) δ 3.84 (s, 3H), 6.85 (dd, 1H), 7.31-7.49 (m,2H), 7.65-7.8 (m, 2H).

Intermediate 78: Methyl (1R,6R and1S,6S)-6-(4-bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylate

Buta-1,3-diene (20 mL, 236.6 mmol), condensed at −78° C., was added to amixture of methyl (2E)-4-(4-bromo-2-fluorophenyl)-4-oxobut-2-enoate(Intermediate 77, 5.5 g, 19.2 mmol) and hydroquinone (0.020 g, 0.18mmol) in toluene (15 mL) at −78° C. and the reaction vessel was sealedand heated at 210° C. for 14 h. The crude product was purified by flashchromatography (5%→30% EtOAc in heptane) to give the title compound(5.69 g, 87%).

¹H NMR (400 MHz, CDCl₃) δ 1.95-2.14 (m, 1H), 2.14-2.27 (m, 1H), 2.49(ddd, 2H), 3.07 (tdd, 1H), 3.56-3.77 (m, 4H), 5.73 (s, 2H), 7.29-7.46(m, 2H), 7.72 (t, 1H).

Intermediate 79: (1R,6R and1S,6S)-6-(4-Bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylic acid

A solution of LiOH (0.40 g, 16.7 mmol) in water (50 mL) was added to asolution of methyl (1R,6R and1S,6S)-6-(4-bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylate(Intermediate 78, 5.6 g, 16.41 mmol) in THF (50 mL) and the reactionmixture was stirred at rt over night. LiOH (0.33 g, 13.8 mmol) was addedto the reaction mixture and it was stirred at rt for 4 h. The reactionmixture was filtered and the filtrate was concentrated under reducedpressure. The crude residue was acidified using HCl (2M, aq) and thewater phase was extracted three times with EtOAc. The combined organicphase was dried over MgSO₄, filtered, and concentrated slightly invacuo. Heptane was added and the solids formed were filtered off anddried to give the title compound (4.19 g, 78%).

¹H NMR (400 MHz, CDCl₃) δ 1.92-2.08 (m, 1H), 2.12-2.36 (m, 1H), 2.33-2.6(m, 2H), 3.06 (td, 1H), 3.64 (td, 1H), 5.72 (s, 2H), 7.3-7.47 (m, 2H),7.70 (t, 1H).

Intermediate 80: (1R,6R or1S,6S)-6-(4-Bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylic acid

The enantiomers of (1R,6R and1S,6S)-6-(4-bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylic acid(Intermediate 79, 8.0 g, 24.5 mmol) were separated by chiral SFCchromatography on a Lux C2 column (5 μm, 250×30 mm). 500 mg (200 mg/mLin MeOH) was injected and eluted with 20% MeOH in CO₂ (g) (175 bar) at aflow rate of 100 mL/min and detected at 265 nm. The first elutedcompound was collected and evaporated to give the title compound (3.95g, 49%, 99.9% ee).

¹H NMR (400 MHz, CDCl₃) δ 1.92-2.06 (m, 1H), 2.19-2.31 (m, 1H), 2.39-2.6(m, 2H), 2.96-3.12 (m, 1H), 3.64 (td, 1H), 5.72 (s, 2H), 7.29-7.44 (m,2H), 7.71 (t, 1H).

Optical rotation: −29.9° (1 g/100 mL in MeCN, 589 nm, 20° C.).

Intermediate 81: 4-({[(1R,6R or1S,6S)-6-(4-Bromo-2-fluorobenzoyl)cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide

T3P (50% in EtOAc, 1 ml, 1.68 mmol) was added to a solution of (1R,6R or1S,6S)-6-(4-bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylic acid(Intermediate 80, 250 mg, 0.76 mmol),4-amino-1-methyl-1H-pyrazole-5-carboxamide (215 mg, 1.53 mmol) and Et₃N(411 μl, 2.96 mmol) in EtOAc (3.5 mL) and the reaction mixture washeated in a microwave reactor at 80° C. for 60 min and then stirred atrt over night. The reaction mixture was diluted with EtOAc and washedtwice with NaHCO₃ (sat. aq) and brine. The organic phase was dried usinga phase separator and concentrated in vacuo. The crude product waspurified by preparative HPLC on a XBridge C18 column (10 μm, 250×19 IDmm) using a gradient of 30-85% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffersystem as mobile phase to give the title compound (140 mg, 41%).

MS m/z 451 [M+2]⁺

Intermediate 82: 4-[({(1R,6R or1S,6S)-6-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]-cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

Pd(dtbpf)Cl₂ (20 mg, 0.03 mmol) was added to a mixture of 4-({[(1R,6R or1S,6S)-6-(4-bromo-2-fluorobenzoyl)cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 81, 140 mg, 0.31 mmol), 1H-pyrazol-5-ylboronic acid (70mg, 0.63 mmol), K₂CO₃ (170 mg, 1.23 mmol) in dioxane (2.5 mL) and water(1.2 mL). The reaction mixture was purged with nitrogen (g) and thenheated in a microwave reactor at 80° C. for 45 min. NaHCO₃ (sat., aq)was added to the reaction mixture and the mixture was extracted withEtOAc. The organic phase was dried using a phase separator, concentratedin vacuo and the crude product was purified by preparative HPLC on aXBridge C18 column (10 μm, 250×19 ID mm) using a gradient of 20-65% MeCNin a H₂O/MeCN/NH₃ (95/5/0.2) buffer system as mobile phase to give thetitle compound (52 mg, 38%).

MS m/z 435.2 [M−H]⁻

Intermediate 83: (1R,2R or1S,2S)-2-(4-Bromo-2-fluorobenzoyl)cyclohexane-carboxylic acid

Rhodium catalyst (5% Rh/C, 628 mg, 0.31 mmol) was added to a solution of(1R,6R or 1S,6S)-6-(4-bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylicacid (Intermediate 80, 10 g, 30.57 mmol) in THF (100 mL) and thereaction mixture was stirred under an atmosphere of hydrogen (2 bar) atrt for 16 h. The crude product was filtered through a pad of celite andthe solids were rinsed with THF. The filtrate was concentrated in vacuoto afford an oil which solidified upon standing. The solid product wasdissolved and precipitated from methyl tert-butylether and heptane, anddried in vacuo to give the title compound (9.16 g, 91%).

¹H NMR (500 MHz, CDCl₃, 23° C.) δ 0.98-1.09 (m), 1.13-1.38 (m, 3H),1.67-1.79 (m, 2H), 1.94 (d, 1H), 2.04-2.13 (m, 1H), 2.73 (t, 1H),3.19-3.29 (m, 1H), 7.18-7.3 (m, 2H), 7.60 (t, 1H).

Intermediate 84: 4-({[(1R,2R or1S,2S)-2-(4-Bromo-2-fluorobenzoyl)cyclohexyl]-carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxamide

4-Amino-1-methyl-1H-pyrazole-3-carboxamide (358 mg, 2.55 mmol) was addedto a solution of (1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexanecarboxylic acid(Intermediate 83, 560 mg, 1.70 mmol), HATU (647 mg, 1.70 mmol) and DIPEA(593 μL, 3.40 mmol) in DMF (3 mL) and the reaction mixture was stirredat rt for 3 h. The crude product was purified by preparative HPLC on aXBridge C18 column (10 μm, 250×19 ID mm) using a gradient of 5-80% MeCNin a H₂O/MeCN/NH₃ (95/5/0.2) buffer system as mobile phase to give thetitle compound (640 mg, 83%).

¹H NMR (500 MHz, CDCl₃) δ 1.24 (qd, 1H), 1.41 (q, 2H), 1.59 (qd, 1H),1.84-1.92 (m, 2H), 2.07-2.2 (m, 2H), 2.81-2.99 (m, 1H), 3.47-3.62 (m,1H), 3.82 (s, 3H), 5.43 (s, 1H), 6.64 (s, 1H), 7.3-7.42 (m, 2H), 7.74(t, 1H), 8.03 (s, 1H), 9.53 (s, 1H).

Intermediate 85: 4-({[(1R,2R or1S,2S)-2-{2-Fluoro-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxamide

K₂CO₃ (262 mg, 1.90 mmol) and Pd(dtbpf)Cl₂ (27 mg, 0.04 mmol) were addedto a solution of 4-({[(1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexyl]carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxamide(Intermediate 84, 214 mg, 0.47 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(198 mg, 0.71 mmol) in dioxane (1.5 mL) and water (1.5 mL). The reactionmixture was evacuated and purged with nitrogen (g) three times, and thenheated in a microwave reactor at 80° C. for 60 min. The reaction mixturewas diluted with EtOAc and the organic phase was washed with NaCl (sat.,aq). The aqueous phase was extracted with EtOAc. The combined organicphase was dried using a phase separator and concentrated under reducedpressure. The crude product was purified by flash chromatography(75%→100% EtOAc in heptane) to give the title compound (273 mg).

MS m/z 521.4 [M−H]⁻

Intermediate 86: 4-({[(1R,2R or1S,2S)-2-{2-Fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxamide

K₂CO₃ (213 mg, 1.54 mmol) and Pd(dtbpf)Cl₂ (22 mg, 0.03 mmol) were addedto a solution of 4-({[(1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexyl]carbonyl}-amino)-1-methyl-1H-pyrazole-3-carboxamide(Intermediate 84, 174 mg, 0.39 mmol) and3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 169 mg, 0.58 mmol) in dioxane (1.5 mL) and water (1.5mL). The reaction mixture was evacuated and purged with nitrogen (g)three times, and then heated in a microwave reactor at 80° C. for 60min. The reaction mixture was diluted with EtOAc and the organic phasewas washed with NaCl (sat., aq). The aqueous phase was extracted withEtOAc and the combined organic phase was dried using a phase separatorand concentrated under reduced pressure. The crude product was purifiedby flash chromatography (75%-*100% EtOAc in heptane) to give the titlecompound (216 mg, 100%).

MS m/z 535.5 [M−H]⁻

Intermediate 87: Ethyl 4-(4-bromo-2-fluorophenyl)-4-hydroxybut-2-ynoate

n-Butyllithium (1.6 M in hexane, 44 mL, 70.4 mmol) was added to asolution of DIPEA (10 mL, 69.2 mmol) in THF (100 mL) under an atmosphereof nitrogen and the reaction mixture was stirred at −78° C. for 30 min.Ethylprop-2-ynoate (6.5 mL, 64.3 mmol) was added dropwise to thereaction mixture followed by the addition of a solution of4-bromo-2-fluorobenzaldehyde (13.1 g, 64.5 mmol) in THF (20 mL). Thereaction mixture was stirred at −78° C. over night. The reaction mixturewas warmed to 0° C., AcOH (15 mL) dissolved in THF (50 mL) was added,followed by water (800 mL). The reaction mixture was extracted threetimes with DCM and the combined organic phase was dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified byflash chromatography (20%→50% EtOAc in heptane) to give the titlecompound (14.7 g, 76%).

¹H NMR (400 MHz, CDCl₃) δ 1.31 (t, 3H), 2.57 (bs, 1H), 4.25 (q, 2H),5.78 (s, 1H), 7.29 (dd, 1H), 7.35 (d, 1H), 7.50 (t, 1H).

Intermediate 88: Ethyl (2E)-4-(4-bromo-2-fluorophenyl)-4-oxobut-2-enoate

Et₃N (14 mL, 101 mmol) was added to a solution of ethyl4-(4-bromo-2-fluorophenyl)-4-hydroxybut-2-ynoate (Intermediate 87, 14.6g, 48.5 mmol) in 1,4-dioxane (40 mL) and the reaction mixture wasstirred at 60° C. for 6 h and then concentrated in vacuo. The residuewas dissolved in EtOAc and the organic phase was washed with HCl (1M,aq) and concentrated in vacuo. The crude compound was purified by flashchromatography (0%→25% EtOAc in heptane) to give the title compound(10.4 g, 71%).

¹H NMR (400 MHz, CDCl₃) δ 1.33 (t, 3H), 4.29 (q, 2H), 6.83 (dd, 1H),7.35-7.45 (m, 2H), 7.67-7.74 (m, 2H).

Intermediate 89: Ethyl (1R,6R and1S,6S)-6-(4-bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylate

Buta-1,3-diene (15 mL, 177.5 mmol), condensed at −78° C., was added to amixture of ethyl (2E)-4-(4-bromo-2-fluorophenyl)-4-oxobut-2-enoate(Intermediate 88, 5.59 g, 18.56 mmol) and hydroquinone (0.035 g, 0.32mmol) in toluene (15 mL) at −78° C., and the reaction vessel was sealedand stirred at rt for 1 h and then heated at 200° C. for 20 h. Thereaction vessel was cooled to −78° C. and buta-1,3-diene (12 mL, 142mmol), condensed at −78° C., was added to the reaction mixture. Thereaction vessel was sealed and heated at 200° C. over night. Thereaction mixture was evaporated in vacuo and the crude product waspurified by flash chromatography (0%→25% EtOAc in heptane) to give thetitle product (5.7 g, 86%).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (t, 3H), 1.89-2.13 (m, 1H), 2.14-2.26 (m,1H), 2.37-2.66 (m, 2H), 3.06 (tdd, 1H), 3.68 (td, 1H), 4.08 (q, 2H),5.73 (s, 2H), 7.3-7.46 (m, 2H), 7.72 (t, 1H).

Intermediate 90: Ethyl (1R,6R and1S,6S)-6-{2-fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohex-3-ene-1-carboxylate

A solution of K₂CO₃ (0.553 g, 4.00 mmol) in degassed water (8 mL) wasadded to mixture of ethyl (1R,6R and1S,6S)-6-(4-bromo-2-fluorobenzoyl)cyclohex-3-ene-1-carboxylate(Intermediate 89, 0.355 g, 1.0 mmol),3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 0.438 g, 1.50 mmol) and Pd(dtbpf)Cl₂ (0.064 g, 0.10mmol) in degassed dioxane (8 mL). The reaction mixture was heated at 90°C. for 1 h and was then partitioned between EtOAc and NaCl (sat., aq).The aqueous phase was extracted with EtOAc and the combined organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by flash column chromatography (15%→60% EtOAcin heptane) to give the title compound (0.355 g, 81%).

¹H NMR (500 MHz, CDCl₃) δ 1.23 (t, 3H), 1.53-1.63 (m), 1.64-1.67 (m,2H), 2.02-2.15 (m, 2H), 2.20-2.29 (m, 1H), (d, 1H), 2.34 (s, 3H),2.44-2.64 (m, 3H), 3.05-3.16 (m, 1H), 3.62 (t, 1H), 3.78 (td, 1H),4.08-4.19 (m, 3H), 5.09-5.15 (m, 1H), 5.76 (s, 2H), 6.20 (s, 1H),7.31-7.41 (m, 2H), 7.89-7.96 (m, 1H).

Intermediate 91: 4-({[(1R,6R and1S,6S)-6-{2-Fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide

Step 1: (1R,6R and1S,6S)-6-{2-Fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohex-3-ene-1-carboxylicacid

A solution of LiOH (0.041 g, 1.70 mmol) in water (2 mL) was added to asolution of ethyl (1R,6R and1S,6S)-6-{2-fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohex-3-ene-1-carboxylate(Intermediate 90, 0.374 g, 0.85 mmol) and the reaction mixture wasstirred at rt over night and then at 60° C. for 6 h. Water was added tothe reaction mixture and the pH was adjusted to ˜4 using KHSO₄ (1M, aq).The aqueous phase was extracted twice with EtOAc and the combinedorganic phase was dried over Na₂SO₄, filtered and concentrated in vacuoto give the subtitle compound (347 mg, 99%).

MS m/z 411.2 [M−H]⁻

Step 2: 4-({[(1R,6R and1S,6S)-6-{2-Fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide

Et₃N (464 μL, 3.35 mmol) and T3P (50% in EtOAc, 598 μL, 1.00 mmol) wereadded to a suspension of (1R,6R and1S,6S)-6-{2-fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohex-3-ene-1-carboxylicacid (Intermediate 91 Step 1, 0.345 g, 0.84 mmol) and4-amino-1-methyl-1H-pyrazole-5-carboxamide (234 mg, 1.67 mmol) in EtOAc(8 mL) and the reaction mixture was stirred at rt over night. DMF (1 mL)was added and the reaction mixture was stirred at rt for 5.5 h. Thereaction mixture was partitioned between EtOAc and NaHCO₃(sat., aq). Theaqueous phase was extracted twice with EtOAc and the combined organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude compound was purified by flash chromatography (EtOAc) to give thetitle compound (191 mg, 43%).

MS m/z 535.1 [M+H]⁺

Intermediate 92: 4-[({(1R,2R and1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

Step 1: 4-[({(1R,6R and1S,6S)-6-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

HCl (4M in dioxane, 59 μL, 0.23 mmol) was added to a solution of4-({[(1R,6R and1S,6S)-6-{2-fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohex-3-en-1-yl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 91, 157 mg, 0.29 mmol) in dioxane (8 mL) and water (2 mL)and the reaction mixture was stirred at rt for 80 min. NaHCO₃ (sat., aq)and EtOAc were added to the reaction mixture and the phases wereseparated. The organic phase was washed with NaHCO₃ (sat., aq). Theaqueous phase was extracted with EtOAc and the combined organic phasewas dried over Na₂SO₄, filtered and concentrated in vacuo to give thesubtitle compound (132 mg, 100%).

MS m/z 449.2 [M−H]⁻

Step 2: 4-[({(1R,2R and1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

Palladium catalyst (5% Pd/C, 62 mg, 0.03 mmol) was added to a solution4-[({(1R,6R and1S,6S)-6-[2-fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 92 Step 1, 0.131 g, 0.29 mmol) in MeOH (4 mL) and EtOAc (4mL) and the reaction mixture was treated to with H₂(g) at 1 atm and atrt over night. The catalyst was filtered off and washed with MeOH. Thefiltrate was concentrated in vacuo and the crude product was purified bypreparative HPLC on a XBridge C18 column (10 μm, 250×19 ID mm) using agradient of 5-70% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system asmobile phase to give the title compound (0.046 g, 35.0%).

¹H NMR (500 MHz, MeOD) δ 1.22 (s, 1H), 1.36-1.68 (m, 3H), 1.88-1.94 (m,2H), 2.10-2.20 (m, 2H), 2.34 (s, 3H), 2.87 (s, 1H), 3.61 (d, 1H), 4.01(s, 3H), 6.54 (s, 1H), 7.48 (s, 1H), 7.59 (d, 2H), 7.86 (d, 1H).

Intermediate 93: (1R,2R or1S,2S)-2-{2-Fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxylicacid

3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 2.08 g, 7.11 mmol) and a degassed solution of K₂CO₃(1.96 g, 14.22 mmol) in water (5 mL) were added to a solution of (1R,2Ror 1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexanecarboxylic acid(Intermediate 83, 1.17 g, 3.55 mmol) in dioxane (5 mL). Pd(dtbpf)Cl₂(0.080 g, 0.12 mmol) was added and the reaction mixture was heated in amicrowave reactor at 60° C. for 50 min. The reaction mixture was dilutedwith water and EtOAc. KHSO₄ (1%, aq) was added to the aqueous layeruntil pH 5 and the aqueous layer was extracted twice with EtOAc. pH ofthe aqueous layer was adjusted to 3-4 and the aqueous layer wasextracted with EtOAc. The combined organic layer was dried using a phaseseparator and concentrated in vacuo. The crude product was purified bypreparative HPLC on a Kromasil C8 column (10 μm, 250×50 ID mm) using agradient of 10-85% MeCN in a H₂O/MeCN/HCO₂H (95/5/0.2) buffer system asmobile phase to give the title compound (1.2 g, 81%).

MS m/z 413.3 [M−H]⁻

Intermediate 94: 4-({[(1R,2R or1S,2S)-2-{2-Fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide

T3P (50% in EtOAc, 194 μL, 0.33 mmol) was added to a suspension of(1R,2R or1S,2S)-2-{2-Fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}-cyclohexanecarboxylicacid (Intermediate 93, 90 mg, 0.22 mmol),4-amino-1H-pyrazole-5-carboxamide hydrochloride (71 mg, 0.43 mmol) andEt₃N (105 μL, 0.76 mmol) in EtOAc (1 mL). DMF (1 mL) was added and thereaction mixture was heated at 80° C. for 3 h. The reaction mixture wasdiluted with NaHCO₃ (8%, aq) and EtOAc. The organic layer was washedthree times with NaHCO₃ (8%, aq), dried using a phase separator andconcentrated in vacuo. The crude product was purified by preparativeHPLC on a XBridge C18 column (10 μm, 250×19 ID mm) using a gradient of10-80% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system as mobil phase togive the title compound (24 mg, 21%).

MS m/z 521.3 [M−H]⁻

Intermediate 95: (1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide

3-Amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride(Intermediate 12, 300 mg, 1.97 mmol), HATU (1.16 g, 3.05 mmol) and Et₃N(768 mg, 7.59 mmol) was added to a solution of (1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexanecarboxylic acid(Intermediate 83, 500 mg, 1.52 mmol) in DMF (20 mL) and the reactionmixture was stirred at 38° C. for 12 h. The reaction mixture wasconcentrated in vacuo and the crude product was purified by silica gelcolumn chromatography (3.8% MeOH in DCM) to give the title compound (300mg, 43%).

MS m/z 463 [M+H]⁺

Intermediate 96: 4-({[(1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexyl]-carbonyl}amino)-1,2,5-oxadiazole-3-carboxamide

T3P (50% in EtOAc, 0.75 ml, 1.26 mmol) was added to a solution of4-amino-1,2,5-oxadiazole-3-carboxamide (0.178 g, 1.39 mmol), (1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexanecarboxylic acid(Intermediate 83, 0.20 g, 0.61 mmol) and DMAP (0.22 g, 1.80 mmol) in THF(2.5 mL) and DCM (0.5 mL) and the reaction mixture was heated in amicrowave reactor at 100° C. for 1 h. The reaction mixture was dilutedwith THF and the crude product was purified by preparative HPLC on aKromasil C18 column, using MeCN in a H₂O/HOAc (100/0.2) buffer system asmobile phase. The product containing fractions were pooled, concentratedin vacuo and freeze-dried to give the title compound (87 mg, 33%).

MS m/z 439.1 [M−H]⁻

Intermediate 97: (1R,2R or1S,2S)-2-(4-Bromo-2-fluorobenzoyl)cyclohexanecarbonyl fluoride

(1R,2R or 1S,2S)-2-(4-Bromo-2-fluorobenzoyl)cyclohexanecarboxylic acid(Intermediate 83, 100 mg, 0.30 mmol) and pyridine (0.052 mL, 0.61 mmol)were dissolved in dry DCM (1 mL) under a nitrogen atmosphere. Thereaction mixture was cooled to −10° C., 2,4,6-trifluoro-1,3,5-triazine(0.051 mL, 0.61 mmol) was added and the reaction mixture was stirred at−10° C. for 2 h. The reaction mixture was diluted with DCM and water wasadded and the reaction mixture was stirred at rt for 30 min. Water andDCM was added and the phases were separated. The combined organic phasewas separated from solids, washed with cold water, dried using a phaseseparator and evaporated at rt in vacuo to give the title compound (107mg, 106%).

¹H NMR (500 MHz, CDCl₃) δ 1.19 (qd, 1H), 1.3-1.5 (m, 2H), 1.50-1.63 (m),1.83-1.97 (m, 2H), 2.14 (d, 1H), 2.23-2.36 (m, 1H), 3.00 (dddd, 1H),3.43 (td, 1H), 7.33-7.45 (m, 2H), 7.75 (t, 1H).

Intermediate 98: 4-({[(1R,2R and1S,2S)-2-(4-Bromobenzoyl)cyclohexyl]carbonyl}-amino)-1-ethyl-1H-pyrazole-3-carboxamide

Et₃N (178 μL, 1.29 mmol) and T3P (50% in EtOAc, 230 μL, 0.39 mmol) wereadded to a suspension of (1R,2R and1S,2S)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (100 mg, 0.32 mmol)and 4-amino-1-ethyl-1H-pyrazole-3-carboxamide (67 mg, 0.43 mmol) inEtOAc (2 mL) and the reaction mixture was heated at 80° C. for 2 h andthen stirred at rt overnight. The reaction mixture was partitionedbetween EtOAc and NaHCO₃(sat., aq). The aqueous phase was extracted withEtOAc and the combined organic phase was dried over Na₂SO₄, filtered,and concentrated in vacuo to give the title compound (119 mg, 83%).

MS m/z 449 [M+2]⁺

Intermediate 99: Ethyl5-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1,3,4-oxadiazole-2-carboxylate

Ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate (1.11 g, 7.06 mmol), T₃P(50% in EtOAc, 8.18 g, 25.72 mmol) and Et₃N (2.6 g, 25.69 mmol) wereadded to a solution of (1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylicacid (2 g, 6.43 mmol) in EtOAc (25 mL) and the reaction mixture washeated at 80° C. for 12 h. The reaction mixture was washed twice withwater and the combined aqueous phase was extracted with EtOAc. Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedin vacuo to give the title compound (2.85 g, 98%).

MS m/z 450 [M+H]⁺

Intermediate 100: (1R,2R and1S,2S)-2-(4-Bromobenzoyl)-N-(3-methyl-1,2-thiazol-5-yl)cyclohexanecarboxamide

T3P (50% in EtOAc, 383 μL, 0.64 mmol) was added to a mixture of (1R,2Rand 1S,2S)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (100 mg, 0.32mmol), 3-methyl-1,2-thiazol-5-amine hydrochloride (97 mg, 0.64 mmol),and Et₃N (134 μL, 0.96 mmol) in EtOAc (3 mL) and the reaction mixturewas heated in a microwave reactor at 150° C. for 30 min. The reactionmixture was diluted with EtOAc and the organic phase was extracted withNaHCO₃ (sat., aq) and brine, dried using a phase separator andconcentrated in vacuo. The crude product was purified flashchromatography (25% EtOAc in toluene) to give the title compound (24 mg,18%).

MS m/z 407.2 [M−H]⁻

Intermediate 101: (1R,2R and1S,1S)-2-(4-Bromobenzoyl)-N-(4-cyano-3-methyl-1,2-thiazol-5-yl)cyclohexanecarboxamide

T3P (50% in EtOAc, 383 μL, 0.64 mmol) was added to a mixture of (1R,2Rand 1S,1S)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (100 mg, 0.32mmol), 5-amino-3-methyl-1,2-thiazole-4-carbonitrile (89 mg, 0.64 mmol),and Et₃N (134 μL, 0.96 mmol) in EtOAc (3 mL) and the reaction mixturewas heated in a microwave reactor at 150° C. for 30 min. The reactionmixture was diluted with EtOAc and the organic phase was extracted withNaHCO₃ (sat., aq) and brine, dried using a phase separator andconcentrated in vacuo. Trituration of the residue from DCM gave thetitle compound (51 mg, 37%).

MS m/z 432.2 [M−H]⁻

Example 1: 1-Methyl-4-[({(1R,2R or1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide

Step 1—Methyl 1-methyl-4-[({(1R,2R and1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxylate

A solution of (1R,2R and1S,2S)-2-(4-(1H-pyrazol-3-yl)benzoyl)cyclohexanecarboxylic acid(Intermediate 1, 200 mg, 0.67 mmol), TBTU (387 mg, 1.21 mmol), methyl4-amino-1-methyl-1H-pyrazole-3-carboxylate (208 mg, 1.34 mmol) and DIPEA(0.351 mL, 2.01 mmol) in NMP (8 mL) was stirred at 50° C. over night.The reaction was quenched by addition of NaHCO₃ (sat, aq). The mixturewas diluted with EtOAc and the phases were separated. The organic layerwas washed with brine, NH₄Cl (sat, aq) and finally brine. The organiclayer was dried over Na₂SO₄, filtered and evaporated leaving thesubtitle compound (292 mg) as a yellow solid.

Step 2—1-Methyl-4-[({(1R,2R and1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxylicacid

A solution of LiOH (1 M aq, 0.80 mL, 0.80 mmol) in water (1.0 mL) wasadded to a solution of crude product of step 1 (292 mg, 0.67 mmol) inMeOH (2.5 mL) and THF (2.5 mL). The resulting solution was stirred at50° C. for 1 h. The mixture was diluted with EtOAc and water and thephases were separated and the water phase was washed with EtOAc. Thecombined water layers were acidified with HCl (6 M) until pH was between4-5 and the product was extracted into EtOAc. The organic layer wasdried over Na₂SO₄, filtered and evaporated to give the subtitle compound(155 mg, 55%) as a slightly brown solid.

MS m/z 420 [M−H]⁻

Step 3—(1R,2R and1S,2S)-1-Methyl-4-[({2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide

A solution of the product from step 2, (155 mg, 0.37 mmol), TBTU (213mg, 0.66 mmol), ammonium chloride (39.3 mg, 0.74 mmol) and DIPEA (0.193mL, 1.10 mmol) in NMP (4 mL) was stirred at 50° C. for 2 h. The reactionwas quenched by addition of NaHCO₃ (sat, aq). The mixture was dilutedwith EtOAc and the phases were separated. The organic layer was washedwith brine, NH₄Cl (sat, aq) and finally brine. The organic layer wasdried over Na₂SO₄, filtered and evaporated leaving a yellow solid whichwas purified by preparative reversed phase HPLC on a XBridge C18 column(5 m OBD 19×150 mm) using a gradient of 5-95% MeCN in H₂O/MeCN/NH₃(95/5/0.2) buffer system at pH10 as mobile phase to give the titlecompound (73 mg, 48%).

¹H NMR (600 MHz, DMSO-d₆) δ 1.21 (d, 1H), 1.44 (t, 1H), 1.52 (td, 2H),1.80 (dd, 2H), 2.01 (dd, 2H), 2.82-2.94 (m, 1H), 3.69-3.78 (m, 1H), 3.80(s, 3H), 6.86 (t, 1H), 7.48 (s, 1H), 7.66 (s, 1H), 7.85 (d, 1H), 7.98(d, 2H), 8.03 (d, 2H), 8.07 (s, 1H), 9.77 (s, 1H), 13.09 (s, majorrotamer), 13.50 (s, minor rotamer). Mixture of rotamers in ratiomajor:minor 1:0.25

MS m/z 421.2 [M+H]⁺

Step 4—1-Methyl-4-[({(1R,2R or1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide

The enantiomers of (1R,2R and1S,2S)-1-methyl-4-[({2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide(50 mg, 0.12 mmol) were separated by chiral chromatography on aChiralpak IA HPLC column (5 μm, 250×20 mm). 50 mg (8 mg/mL in EtOH:DCM,4:2) was injected and eluted with EtOH:DCM (4:2) at a flow rate of 15mL/min and detected at 245 nm. The first eluted compound was collectedand evaporated to give the title compound (0.019 g, 99.6% ee).

HRMS m/z 841.3857 [2M+H]⁺

Example 2:1-Methyl-4-[({(1R,2R)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-5-carboxamide

4-({[(1R,2R)-2-(4-Bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 2, 130 mg, 0.30 mmol), 1H-pyrazol-3-ylboronic acid (70 mg,0.63 mmol), K₂CO₃ (170 mg, 1.23 mmol) and Pd(dtbpf)Cl₂ (20 mg, 0.03mmol) were mixed in dioxane (2.5 mL) and H₂O (1.2 mL) and the reactionmixture was purged with nitrogen. The reaction mixture was heated in amicrowave reactor at 80° C. for 45 min. NaHCO₃ (sat, aq) was added andthe mixture was extracted with EtOAc. The organic phase was dried usinga phase separator and the solvent evaporated. The crude product waspurified by preparative HPLC on a XBridge C18 column (10 μm 250×19 IDmm) using a gradient of 20-65% acetonitrile in H₂O/MeCN/NH₃ (95/5/0.2)buffer system as mobile phase. The desired fractions were collected andthe solvent evaporated to give the title compound (36 mg, 28%).

¹H NMR (400 MHz, CDCl₃) δ 1.19-1.43 (m, 3H), 1.50 (dd, 1H), 1.73 (dt,1H), 1.8-1.97 (m, 2H), 2.10 (d, 2H), 2.84-2.96 (m, 1H), 4.02 (s, 3H),6.66 (dd, 4H), 7.53 (s, 1H), 7.6-7.66 (m, 1H), 7.80 (d, 2H), 7.94 (t,2H), 8.23 (s, 1H).

MS m/z 421 [M+H]⁺

Example 3:1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-5-carboxamide

HCl in MeOH (6.0 mL, 7.20 mmol) was added to a solution of1-methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]-carbonyl}amino)-1H-pyrazole-5-carboxamide(Intermediate 4, 1.39 g, 2.68 mmol) in MeOH (230 mL). The resultingsolution was evaporated in vacuo at 5° C. The residue was dissolved in230 mL MeOH and evaporated again at 5° C. and the crude product wasimmediately purified by preparative HPLC on a XBridge C18 column (10 μm250×19 ID mm) using a gradient of 5-70% MeCN in H₂O/MeCN/NH₃ (95/5/0.2)buffer system as mobile phase. The desired fractions were collected andfreeze-dried and repurifed by preparative SFC on a Luna HILIC column (5μm 250×30 ID mm) using 25% MeOH/DEA (100/0.5) in CO₂(g) (150 bar) asmobile phase. The desired fractions were collected, evaporated andfreeze-dried from MeCN/H₂O (1:1) to give the title compound (0.71 g,67%).

¹H NMR (500 MHz, DMSO) δ 1.17 (dd, 1H), 1.29-1.39 (m, 1H), 1.42-1.57 (m,2H), 1.72-1.88 (m, 2H), 1.97 (d, 1H), 2.07 (d, 1H), 2.78-2.91 (m, 1H),3.29 (s, 3H), 3.65-3.74 (m, 1H), 3.89 (s, 3H), 6.56 (s, 1H), 7.89 (d,2H), 7.99 (d, 2H), 9.49 (s, 1H), 12.74 (s, 1H)

Example 4:1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide

Step1—1-Methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-3-carboxamide

3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 283 mg, 0.97 mmol) and a degassed solution of K₂CO₃ (89mg, 0.65 mmol) in water (1 mL) was added to a solution of4-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxamide(Intermediate 6, 70 mg, 0.16 mmol) in dioxane (1 mL). Pd(dtbpf)Cl₂(10.40 mg, 0.02 mmol) was added and the resulting mixture was heated ina microwave reactor at 85° C. for 60 min. The reaction mixture wasdiluted with EtOAc and washed with brine (sat.). The aqueous phase wasextracted twice with EtOAc. The combined organic phase was dried using aphase separator and concentrated. The residue was purified by flashchromatography (100% EtOAc) to give the subtitle compound (118 mg,141%).

MS m/z 517 [M−H]⁻

Step2—1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide

HCl (1.2 M in MeOH) (1 mL, 1.20 mmol) was added to a solution of theproduct from step 1 (118 mg, 0.23 mmol) in MeOH (10 mL) and the reactionmixture was concentrated at 5° C. The residue was dissolved in 10 mLMeOH and concentrated at 5° C. The compound was immediately purified bypreparative HPLC on a XBridge C18 column (10 μm 250×19 ID mm) using agradient of 5-70% MeCN in H₂O/MeCN/NH₃ (95/5/0.2) buffer system asmobile phase to give the title compound (46 mg, 46%).

¹H NMR (500 MHz, DMSO-d₆) δ 1.19 (q, 1H), 1.35-1.56 (m, 3H), 1.75 (d,2H), 1.81 (d, 1H), 1.95 (d, 1H), 2.01 (d, 1H), 2.28 (s, 3H), 2.8-2.93(m, 1H), 3.68-3.77 (m, 1H), 3.78 (s, 3H), 6.56 (s, 1H), 7.47 (s, 1H),7.64 (s, 1H), 7.89 (d, 2H), 8.00 (d, 2H), 8.05 (s, 1H), 9.75 (s, 1H),12.75 (s, major rotamer), 13.08 (s, minor rotamer). Mixture of rotamersin ratio major:minor 1:0.19.

MS m/z 435.3 [M+H]⁺

Example 5a: (1S,2S or1R,2R)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamideand Example 5b: (1R,2R or1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

Step 1—(1R,2R and1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxamide

((1R,2R and1S,2S)-2-(4-Bromobenzoyl)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)cyclohexanecarboxamide(Intermediate 7, 150 mg, 0.36 mmol) and3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 106 mg, 0.36 mmol) were dissolved in dioxane:DMF (2 mL,95:5). Pd(dtbpf)Cl₂ (7.0 mg, 11 μmol) and a solution of K₂CO₃ (200 mg,1.44 mmol) in water (1.5 mL) were added and the reaction mixture wasevacuated and purged with nitrogen three times and then heated at 80° C.for 45 min. The reaction mixture was used directly in Step 2.

Step 2—(1R,2R and1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

HCl (2 M in dioxane:water, 1:1, 1 mL) was added to the reaction mixturefrom Step 1 above and the reaction mixture was stirred at rt for 15 min.The reaction mixture was concentrated and the residue was diluted withEtOAc and washed with NaHCO₃ (sat, aq). The aqueous phase was extractedwith EtOAc and the combined organic phase was washed with NH₄Cl (aq) andbrine. The organic layer was dried using a phase separator and thesolvent was removed under vacuum. The compound was purified bypreparative HPLC on a XBridge C18 column (10 μm 250×19 ID mm) using agradient of 20-65% MeCN in H₂O/MeCN/NH₃ (95/5/0.2) buffer system asmobile phase to give the subtitle Step 2 compounds (102 mg, 68%) as awhite solid.

¹H NMR (500 MHz, DMSO-d₆) δ 1.1-1.23 (m, 1H), 1.33 (t, 1H), 1.37-1.58(m, 2H), 1.72-1.80 (m), 1.83 (d, 1H), 1.97 (d, 1H), 2.07 (d, 1H), 2.27(s, 3H), 2.88-3.01 (m, 1H), 3.74 (t, 1H), 3.81 (s, 3H), 6.56 (s, 1H),7.88 (d, 2H), 8.00 (d, 2H), 8.10 (s, 1H), 10.41 (s, 1H), 12.75 (s, 1H)

MS m/z 417.1 [M+H]⁺

Step 3—(1R,2R or1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamideand (1S,2S or1R,2R)—N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexanecarboxamide

The enantiomers of (1R,2R and1S,2S)—N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide(77 mg, 0.18 mmol) were separated by chiral chromatography on aChiralpak AD column (5 μm, 250×20 mm). 52 mg (26 mg/mL in EtOH:DCM, 2:1)was injected and eluted with Heptane:EtOH (30:70) at a flow rate of 18mL/min and detected at 260 nm. The first eluted compound was collectedand evaporated to give Example 5a (31 mg, 40%, 98.2% ee).

¹H NMR (500 MHz, CDCl₃) δ 1.26-1.6 (m, 3H), 1.72 (td, 1H), 1.83-1.98 (m,2H), 2.11 (td, 2H), 2.39 (s, 3H), 2.92 (ddd, 1H), 3.68-3.79 (m, 1H),3.83 (s, 3H), 5.31 (s, 1H), 6.44 (s, 1H), 7.80-7.86 (m, 3H), 7.98-8.03(m, 3H) Optical rotation: −138.9° (1 g/100 mL in MeCN, 589 nm, 20° C.).

The second eluted compound was collected and evaporated to give Example5b (30 mg, 39%, 98.6% ee) Optical rotation: +136.8° (1 g/100 mL in MeCN,589 nm, 20° C.).

¹H NMR (500 MHz, CDCl₃) δ 1.27-1.56 (m, 3H), 1.65-1.76 (m, 1H),1.85-1.97 (d, 2H), 2.11 (t, 2H), 2.39 (s, 3H), 2.87-2.95 (m, 1H),3.69-3.78 (m, 1H), 3.84 (s, 3H), 5.31 (s, 2H), 6.44 (s, 1H), 7.79 (s,1H), 7.83 (d, 2H), 7.98-8.04 (m, 3H)

Example 6:(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1H-pyrazol-4-yl)cyclohexanecarboxamide

Step1—(1R,2R)-2-{4-[3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}-N-(1H-pyrazol-4-yl)cyclohexanecarboxamide

(1R,2R)-2-{4-[3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}-cyclohexanecarboxylicacid (Intermediate 8, 0.167 g, 0.42 mmol) was added to a mixture of1H-pyrazol-4-amine (0.074 g, 0.89 mmol), T3P (50% in EtOAc, 0.37 mL,0.63 mmol) and Et₃N (0.23 mL, 1.68 mmol) in EtOAc (8 mL) and thereaction mixture was stirred at rt for 30 min. DMF (1 mL) was added andthe reaction mixture was stirred at rt over night. 1H-Pyrazol-4-amine(0.040 g), T3P (50% in EtOAc, 0.150 mL, 0.25 mmol) and DMF (2 mL) wasadded and the reaction mixture was stirred at rt for 1 h. The reactionmixture was diluted with EtOAc and the organic phase was washed twicewith NaHCO₃ (sat, aq). The organic phase was dried over MgSO₄, filteredand concentrated in vacuo to give the subtitle compound (0.194 g 100%).

MS m/z 460.3 [M−H]⁻

Step2—(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1H-pyrazol-4-yl)cyclohexanecarboxamide

HCl (2 M HCl in dioxane/water, 1:1, 2 mL) was added to the compound fromstep 1 (194 mg, 0.42 mmol) and the reaction mixture was stirred at rtfor 30 min. The reaction mixture was diluted with EtOAc and the organicphase was washed with NaHCO₃ (sat, aq). The aqueous phase was extractedonce with EtOAc and the combined organic phase was dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified bypreparative HPLC on a XBridge C18 column (5 μm OBD 19×150 mm) using agradient of 5-95% MeCN in H₂O/MeCN/NH₃ (95/5/0.2) buffer system at pH10as mobile phase to give the title compound (52 mg, 33%).

¹H NMR (600 MHz, DMSO-d₆) δ 1.08-1.2 (m, 1H), 1.27-1.37 (m, 1H),1.40-1.54 (m, 2H), 1.71-1.79 (m, 1H), 1.79-1.86 (m, 1H), 1.92-1.98 (m,1H), 1.99-2.07 (m, 1H), 2.28 (s, 3H), 2.75-2.83 (m, 1H), 3.68-3.76 (m,1H), 6.56 (s, 1H), 7.38 (s, 1H), 7.70 (s, 1H), 7.90 (d, 2H), 7.99 (d,2H), 9.99 (s, 1H), 12.45 (s, 1H), 12.75 (s, major rotamer), 13.10 (s,minor rotamer). Mixtures of rotamers in ratio major:minor 1:0.18.

MS m/z 378.2 [M+H]⁺

Example 7:(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide

HCl (6 M in water, 20 mL) was added slowly to a solution of(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(Intermediate 14, 3.5 g, 6.60 mmol) in dioxane (40 mL) and water (10 mL)at 4° C. over a period of 2 min. The reaction mixture was stirred at 5min at 4° C. and was then allowed to reach rt and stirred for 1 h. Thesolvent was removed under vacuum. The residue was diluted with asolution of Na₂CO₃ (sat, aq) and the aqueous layer was extracted threetimes with DCM. The solvent was removed under vacuum and the crudeproduct was purified by reversed phase flash chromatography on a C18column using a gradient of 25-45% MeCN in H₂O/HCO₂H (99.9/0.1) buffersystem as mobile phase. Pure fractions were collected and evaporated todryness to afford the title compound (1.8 g, 61%) as a light yellowsolid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.10-1.55 (m, 4H), 1.74-1.82 (m, 2H),1.95-2.08 (m, 2H), 2.28 (s, 3H), 2.99 (t, 1H), 3.70 (s, 2H), 3.82 (t,1H), 4.21 (t, 2H), 6.58 (s, 1H), 7.82 (s, 1H), 7.90 (d, 2H), 8.01 (d,2H), 8.33 (s, 1H), 9.15 (s, 1H), 12.76 (s, 1H)

MS m/z 469 [M+Na]⁺

Example 8:(1R,2R)—N-[1-Methyl-5-(methylsulfonyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

(1H-Pyrazol-3-yl)boronic acid (108 mg, 0.97 mmol), Pd(dppf)Cl₂*DCM (105mg, 0.13 mmol) and a solution of K₂CO₃ (266 mg, 1.92 mmol) in water (1.5mL) was added to a solution of(1R,2R)-2-(4-Bromobenzoyl)-N-[1-methyl-5-(methylsulfonyl)-1H-pyrazol-4-yl]cyclohexanecarboxamide(Intermediate 18, 300 mg, 0.66 mmol) in dioxane (10 mL) under anatmosphere of nitrogen. The reaction mixture was stirred at 100° C. for1.5 h under an atmosphere of nitrogen. A solution of water/EtOAc (1:10)was added to the reaction mixture and the solids were filtered out. Theorganic layer was washed with water and brine, dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bypreparative TLC (95% DCM in MeOH). The crude product was purified bypreparative HPLC on a Sunfire C18 column (19×150 mm) using a gradient of5-40% MeCN in H₂O/HCO₂H (99.9/0.1) buffer system as mobile phase to givethe title compound (120 mg, 41%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.11-1.23 (m, 1H), 1.53-1.32 (m, 3H),1.73-1.85 (m, 2H), 1.94 (d, 1H), 2.07-2.11 (m, 1H), 2.86-2.93 (t, 1H),3.41 (s, 3H), 3.71-3.76 (t, 1H), 3.99 (s, 3H), 6.83 (s, 1H), 7.73 (s,1H), 7.83-8.13 (m, 5H), 9.19 (s, 1H), 13.07 (s, major rotamer), 13.51(s, minor rotamer). Mixture of rotamers in ratio major:minor 1:0.23.

MS m/z 456 [M+H]⁺

Example 9:(1R,2R)—N-[3-(Difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

A solution of K₂CO₃ (121 mg, 0.88 mmol) in water (2 mL),1H-pyrazol-3-ylboronic acid (74 mg, 0.66 mmol) and Pd(dppf)Cl₂*DCM (72mg, 0.09 mmol) was added to a solution of(1R,2R)-2-(4-bromobenzoyl)-N-[3-(difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]cyclohexanecarboxamide(Intermediate 21, 200 mg, 0.44 mmol) in dioxane (10 mL) and the reactionmixture was stirred at 80° C. for 1 h. The reaction mixture wasconcentrated under vacuum and the residue purified by silica gel columnchromatography (10%→50% EtOAc in petroleum ether) and then bypreparative HPLC on a T3 column, using MeCN in H₂O/HCO₂H (99.9/0.1) asmobile phase to give the title compound (125 mg, 64%) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ1.26-2.10 (m, 8H); 2.86 (t, 1H), 3.66 (s, 3H),3.75 (t, 1H), 6.26 (br, 1H), 6.72 (s, 1H), 6.78 (t, 1H), 7.25 (s, 3H),7.66 (s, 1H), 7.75 (s, 1H), 7.87 (d, 2H), 8.05 (d, 2H)

MS m/z 444 [M+H]⁺

Example 10:(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-3-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide

(5-Methyl-1H-pyrazol-3-yl)boronic acid hydrochloride (Intermediate 31,209 mg, 1.29 mmol), Pd(dppf)Cl₂*DCM (70 mg, 0.09 mmol) and K₂CO₃ (206mg, 1.49 mmol) was added to a solution of(1R,2R)-2-(4-bromobenzoyl)-N-(1-methyl-3-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide(Intermediate 25, 200 mg, 0.43 mmol) in a mixture of dioxane H₂O (15 mL)under an atmosphere of nitrogen and the reaction mixture was stirred at50° C. for 3 h. The reaction mixture was extracted twice with EtOAc andthe combined organic layer was washed three times with water, dried overNa₂SO₄, filtered and concentrated under vacuum. The crude residue waspurified by preparative HPLC on an XBridge C18 OBD column (5 μm 150×19ID mm) using a gradient of 18-90% MeCN in NH₄HCO₃ (0.010 M, aq) buffersystem as mobile phase to give the title compound (54 mg, 27%) as awhite solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.10-1.26 (m, 1H), 1.37-1.55 (m, 3H),1.77-1.87 (m, 2H), 1.96-2.05 (m, 2H), 2.30 (s, 3H), 2.51 (t, 1H), 2.93(t, 1H), 3.80 (s, 3H), 6.57 (s, 1H), 7.58 (s, 2H), 7.92 (d, 2H), 8.03(d, 2H), 8.12 (s, 1H), 8.92 (s, 1H), 12.74 (s, major rotamer), 13.1 (s,minor rotamer). Unknown ratio of rotamers.

MS m/z 471 [M+H]⁺

Example 11:(1R,2R)—N-(2,3-Dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

K₂CO₃ (132 mg, 0.96 mmol) and Pd(dppf)Cl₂*DCM (78 mg, 0.10 mmol) wereadded to a solution of(1R,2R)-2-(4-bromobenzoyl)-N-(2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)cyclohexanecarboxamide(Intermediate 30, 200 mg, 0.48 mmol) and(5-methyl-1H-pyrazol-3-yl)boronic acid (60 mg, 0.48 mmol) in 1,4-dioxane(5 mL) and water (1 mL) at rt and the reaction mixture was heated at 80°C. for 5 h under an atmosphere of nitrogen. The solvent was removedunder vacuum and the residue was dissolved in EtOAc. The organic layerwas washed twice with water, dried over Na₂SO₄, filtered and evaporated.The residue was purified by preparative TLC (9% MeOH in DCM), then byC18-flash chromatography (0%→50% MeCN in water) to give the titlecompound (60 mg, 30%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.20-1.01 (m, 1H). 1.41-1.49 (m, 3H),1.73-1.82 (m, 2H), 1.90-2.03 (m, 2H), 2.50 (s, 3H), 2.78 (t, 1H), 3.68(t, 1H), 4.18 (t, 2H), 4.99 (t, 2H), 6.56 (s, 1H), 7.21 (s, 1H), 7.89(d, 2H), 7.98 (d, 2H), 9.35 (s, 1H), 12.75 (s, major rotamer), 13.1 (s,minor rotamer). Unknown ratio of rotamers.

MS m/z 420 [M+H]⁺

Example 12: (1R,2R or1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

Step 1—(1R,2R and1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

(1R,2R and1S,2S)-2-(4-Bromobenzoyl)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)cyclohexanecarboxamide(Intermediate 7, 150 mg, 0.36 mmol) was dissolved in dioxane (1.5 mL).1H-Pyrazol-3-ylboronic acid (73 mg, 0.65 mmol), Pd(dppf)Cl₂*DCM (29 mg,0.04 mmol) and a solution of K₂CO₃ (0.065 mL, 1.1 mmol) in water (1.5mL) were added and the reaction mixture was evacuated and purged withnitrogen three times and then heated in a microwave reactor at 60° C.for 30 min and then at 80° C. for 50 min. The reaction mixture wasdiluted with EtOAc and the organic phase was washed twice with asolution of brine (sat.). The aqueous phase was extracted twice withEtOAc. The combined organic phase was dried using a phase separator andconcentrated and the residue was purified by preparative HPLC on aXBridge C18 column (10 μm 250×19 ID mm) using a gradient of 20-65% MeCNin a H₂O/MeCN/NH₃ (95/5/0.2) buffer system as mobile phase to give thesub-title compounds (45 mg 31%).

¹H NMR (600 MHz, DMSO-d₆) δ 1.16 (qd, 1H), 1.27-1.38 (m, 1H), 1.39-1.55(m, 2H), 1.72-1.79 (m, 1H), 1.82 (d, 1H), 1.95 (d, 1H), 2.02 (d, 1H),2.28 (s, 3H), 2.74-2.84 (m, 1H), 3.65-3.78 (m, 1H), 6.56 (s, 1H), 7.40(s, 1H), 7.70 (s, 1H), 7.89 (d, 2H), 7.99 (d, 2H), 9.99 (s, 1H), 12.45(s, 1H), 12.75 (s, rotamer), 13.09 (s, rotamer)

MS m/z 403.1 [M+H]⁺

Step 2—(1R,2R or1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

The enantiomers from step 1 (30 mg, 0.07 mmol) were separated by chiralchromatography on a Chiralpak AD column (5 μm, 250×20 mm). 30 mg (30mg/mL in EtOH:DCM, 91:9) was injected and eluted with Heptane:EtOH(30:70) at a flow rate of 18 mL/min and detected at 260 nm. The secondeluted compound was collected and evaporated to give the title compound(11 mg, 37%, 99.9% ee).

¹H NMR (500 MHz, CDCl₃) δ 1.25-1.45 (m, 2H), 1.50 (ddd, 1H), 1.69 (qd,1H), 1.84-1.95 (m, 2H), 2.05-2.17 (m, 2H), 2.96 (ddd, 1H), 3.73-3.83 (m,4H), 6.70 (d, 1H), 7.67 (d, 1H), 7.87 (d, 2H), 7.99 (s, 1H), 8.04 (d,2H), 8.22 (s, 1H).

Optical rotation: −153.8° (1 g/100 mL in MeCN, 589 nm, 20° C.).

Example 13:(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide

PdCl₂(dppf)-DCM (4.87 g, 5.97 mmol) was added to a mixture of(1R,2R)-2-(4-bromobenzoyl)-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide(Intermediate 37, 28 g, 59.7 mmol), (5-methyl-1H-pyrazol-3-yl)boronicacid (15.02 g, 119.31 mmol) and sodium carbonate (25.3 g, 238.63 mmol)in dioxane (500 mL) and water (125 mL) under nitrogen atmosphere and thereaction mixture was stirred at 85° C. for 4 h. The reaction mixture wasconcentrated under vacuum and diluted with EtOAc and the organic phasewas washed with brine (sat., aq), dried over Na₂SO₄, filtered andevaporated. The crude product was purified by Flash columnchromatography on a C18 column (32 μm, 400 g), using a gradient from0-40% of MeCN in water as mobile phase to give the title compound (12.73g, 45.3%) as a brown solid.

¹H-NMR (300 MHz, DMSO-d₆) δ 1.13-1.22 (m, 1H), 1.36-1.52 (m, 3H),1.74-1.84 (m, 2H), 1.96-2.08 (m, 2H), 2.22 (d, 3H), 2.84-2.90 (m, 1H),3.35-3.75 (m, 1H), 3.92 (d, 3H), 6.57 (s, 1H), 7.81 (s, 1H), 7.89-7.96(t, 2H), 8.01-8.16 (m, 4H), 8.82 (s, 1H), 12.78 (s, 1H).

MS m/z 471 [M+H]⁺

Example 14: (1R,2R and1S,2S)—N-(5-Methoxy-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

Step 1—(1R,2R and1S,2S)-2-(4-bromobenzoyl)-N-(5-methoxy-1-methyl-1H-pyrazol-4-yl)cyclohexanecarboxamide

(1R,2R and 1S, 2S)-2-(4-Bromobenzoyl)cyclohexanecarboxylic acid (59 mg,0.19 mmol), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (61.3mg, 0.37 mmol) and Et₃N (105 μl, 0.76 mmol) were suspended in EtOAc (2.1mL). T3P (50% in EtOAc, 135 μL, 0.23 mmol) was added and the reactionmixture was heated in a microwave reactor at 100° C. for 20 min. Themixture was partitioned between EtOAc and NaHCO₃ (sat., aq) and theorganic phase was washed with NH₄Cl (sat., aq) and brine. The organicphase was dried using a phase separator and concentrated under vacuum togive the subtitle compound (63 mg, 79%).

MS m/z 420 [M+H]⁺

Step 2—(1R,2R and1S,2S)—N-(5-methoxy-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

K₂CO₃ (83 mg, 0.60 mmol) and Pd(dppf)Cl₂*DCM (12 mg, 0.01 mmol) wereadded to a solution of the product of step 1 (63 mg, 0.15 mmol) and1H-pyrazol-3-ylboronic acid (25 mg, 0.22 mmol) in dioxane (0.7 mL) andwater (0.7 mL). The mixture was evacuated and purged with nitrogen threetimes and then heated in a microwave reactor at 100° C. for 30 min. Thereaction mixture was diluted with EtOAc and water and the aqueous phasewas extracted once with EtOAc. The combined organic layer was washedwith brine, NH₄Cl (sat., aq), brine, dried using a phase separator andconcentrated under vacuum. The crude product was purified by preparativeHPLC on a XBridge C18 column (5 m 150×19 ID mm) using a gradient of5-95% of MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system as mobile phaseto give the title compound (11 mg 18%).

¹H NMR (600 MHz, DMSO-d₆) δ 1.1-1.2 (m, 1H), 1.26-1.35 (m, 1H),1.36-1.44 (m, 1H), 1.45-1.54 (m, 1H), 1.72-1.83 (m, 2H), 1.91-1.97 (m,1H), 2-2.06 (m, 1H), 2.91-2.97 (m, 1H), 3.56 (s, 3H), 3.69-3.75 (m, 1H),3.81 (s, 3H), 6.85 (d, 1H), 7.64 (s, 1H), 7.83 (s, 1H), 7.92-8.07 (m,4H), 9.44 (s, 1H), 13.08 (s, 1H).

MS m/z 408.2 [M+H]⁺

Example 15:(1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

Step1—(1R,2R)—N-[5-(Difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

(5-Methyl-1H-pyrazol-3-yl)boronic acid (237 mg, 1.88 mmol), K₂CO₃ (650mg, 4.70 mmol), and Pd(dppf)Cl₂*DCM (128 mg, 0.16 mmol) were added to asolution of(1R,2R)-2-(4-bromobenzoyl)-N-[5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanecarboxamide(Intermediate 39, 800 mg, 1.57 mmol) in a mixture of dioxane and water(4:1, 15 mL) under an atmosphere of nitrogen, and the reaction mixturewas stirred at 50° C. for 2 h. The reaction mixture was diluted withEtOAc and the organic phase was washed with water, brine (sat.), driedover Na₂SO₄, and concentrated under vacuum. The residue was purified bysilica gel column chromatography (33% EtOAc in petroleum ether) to givethe subtitle compound (620 mg, 77%) as a yellow solid.

MS m/z 512 [M+H]⁺

Step2—(1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

HCl (3M in MeOH, 5.9 mL) was added to a solution of the product fromstep 1 (600 mg, 1.17 mmol) in MeOH (30 mL) and the reaction mixture wasstirred at rt for 1 h. The pH value of the reaction mixture was adjustedto ˜8 using NaHCO₃ (aq), and the reaction mixture was extracted withEtOAc. The organic layer was washed with brine (sat.), dried over Na₂SO₄and concentrated under vacuum. The crude product was purified bypreparative HPLC on a XBridge Prep C18 OBD column (5 μm, 150×19 ID mm)using a gradient of 25-55% of MeCN in water (0.03% NH₄OH) as mobilephase to give the title compound (69 mg, 14%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆) δ 1.34-1.38 (m, 1H), 1.41-1.53 (m, 3H),1.73-1.84 (m, 2H), 1.94-2.07 (m, 2H), 2.27 (s, 3H), 2.93-2.96 (m, 1H),3.69-3.76 (m, 1H), 6.56 (s, 1H), 6.99 (t, J=54.0 Hz, 1H), 7.89-8.07 (m,5H), 9.67 (s, 1H), 12.74 (s, 1H), 13.04 (s, 1H).

MS m/z 428 [M+H]⁺

Example 16:(1R,2R)—N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

Pd(dppf)Cl₂*DCM (53 mg, 0.07 mmol) was added to(1R,2R)-2-(4-bromobenzoyl)-N-(5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(Intermediate 42, 300 mg, 0.65 mmol), (5-methyl-1H-pyrazol-3-yl)boronicacid (164 mg, 1.31 mmol) and Na₂CO₃ (138 mg, 1.31 mmol) in 1,4-dioxane(10 mL) and water (1 mL) at 25° C. under an atmosphere of nitrogen andthe reaction mixture was stirred at 90° C. for 15 h. Pd(dppf)Cl₂*DCM (26mg, 0.035 mmol), (5-methyl-1H-pyrazole-3-yl)boronic acid (80 mg, 0.65mmol) and Na₂CO₃ (70 mg, 0.65 mmol) were added to the reaction mixtureand it was stirred at 90° C. for 6 h. The reaction mixture was dilutedwith EtOAc (50 mL), filtered through a pad of celite and concentratedunder vacuum. The crude residue was purified by preparative TLC (5% MeOHin DCM). The crude product was purified by preparative HPLC on a XBridge C18, column (5 μm 19×150 mm ID) using a gradient of 30-70% ofMeCN in a H₂O/CF₃CO₂H (99.95/0.05) buffer system as mobile phase, togive the title compound (130 mg, 43%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.10-1.55 (m, 4H), 1.70-1.85 (m, 2H),1.95-2.10 (m, 2H), 2.30 (s, 3H), 2.98 (t, 1H), 3.02 (s, 3H), 3.70 (t,1H), 3.78 (t, 2H), 4.30 (t, 2H), 6.52 (s, 1H), 7.82 (s, 1H), 7.90 (d,2H), 8.00 (d, 2H), 9.20 (s, 1H), 12.78 (s, 1H)

MS m/z 461 [M+H]⁺

Example 17:(1R,2R)—N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

Pd(dppf)Cl₂*DCM (53.3 mg, 0.07 mmol) was added to a mixture of(1R,2R)-2-(4-bromobenzoyl)-N-(5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(Intermediate 42, 300 mg, 0.65 mmol), 1H-pyrazol-3-ylboronic acid (146mg, 1.31 mmol) and Na₂CO₃ (138 mg, 1.31 mmol) in 1,4-dioxane (10 mL) andwater (1 mL) at 25° C. under an atmosphere of nitrogen and the reactionmixture was stirred at 90° C. for 15 h. Pd(dppf)Cl₂*DCM (27 mg, 0.035mmol), (1H-pyrazol-3-yl)boronic acid (73 mg, 0.65 mmol) and Na₂CO₃ (70mg, 0.65 mmol) were added and the reaction mixture was stirred at 90° C.for 6 h. The reaction mixture was diluted with EtOAc (50 mL), filteredthrough a pad of celite and concentrated under vacuum. The residue waspurified by preparative TLC (5% MeOH in DCM). The crude product waspurified by preparative HPLC on a X Bridge C18 column (5 μm, 19×150 mmID) using a gradient of 30-70% of MeCN in water (0.05% CF₃COOH) asmobile phase, to give the title compound (130 mg, 45%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.10-1.60 (m, 4H), 1.70-1.85 (m, 2H),1.90-2.10 (m, 2H), 2.99 (t, 1H), 3.01 (s, 3H), 3.74 (t, 1H), 3.79 (t,2H), 4.20 (t, 2H), 6.88 (s, 1H), 7.85 (s, 2H), 8.01 (d, 2H), 8.08 (d,2H), 9.20 (s, 1H), 13.10 (s, 1H).

MS m/z 447 [M+H]⁺

Example 18a: (1R,2R or1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamideand Example 18b: (1S,2S or1R,2R)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

Step 1—(1R,2R and1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

1H-Pyrazol-3-ylboronic acid (73 mg, 0.65 mmol), Pd(dppf)Cl₂*DCM (8.8 mg,10.8 μmol) and a solution of K₂CO₃ (149 mg, 1.08 mmol) in water (1.5 mL)were added to a mixture of (1R,2R and1S,2S)-2-(4-bromobenzoyl)-N-(5-cyano-1-methyl-1H-pyrazol-4-yl)cyclohexanecarboxamide(Intermediate 43, 150 mg, 0.36 mmol) in dioxane (1.5 mL) and thereaction mixture was evacuated and purged with nitrogen and then heatedat 80° C. for 3.5 h. The reaction mixture was diluted with EtOAc and theorganic phase was washed to twice with brine (sat.). The aqueous phasewas extracted twice with EtOAc and the combined organic phase was driedusing a phase separator and concentrated in vacuum. The residue waspurified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm,19×150 mm ID) using a gradient of 5-95% of MeCN in a HCO₂H (0.1M, aq)buffer system as a mobile phase. The product containing fractions wereconcentrated and dissolved in EtOAc. The organic phase was washed withbrine, dried using a phase-separator and concentrated in vacuum to givethe title compound (46 mg, 32%).

¹H NMR (500 MHz, DMSO-d₆) δ 1.1-1.23 (m, 1H), 1.33 (t, 1H), 1.39-1.62(m, 2H), 1.80 (dd, 2H), 1.94-2.02 (m, 1H), 2.06 (d, 1H), 2.83-2.98 (m,1H), 3.69-3.79 (m, 1H), 3.89 (s, 3H), 6.84 (d, 1H), 7.70 (s, 1H),7.9-8.13 (m, 4H), 10.52 (s, 1H), 13.08 (s, 1H)

MS m/z 403 [M+H]⁺

Step 2—(1R,2R or1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide(18a) and (1S,2S or1R,2R)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide(18b)

The enantiomers from step 1 (34 mg, 0.08 mmol) were separated by chiralchromatography on a Chiralpak AD column (5 μm, 250×20 mm). 34 mg (17mg/mL in EtOH) was injected and eluted with Heptane:EtOH (30:70) at aflow rate of 18 mL/min and detected at 260 nm. The first eluted compoundwas collected and evaporated to give Example 18a (13 mg, 38%, 98% ee).

Optical rotation: −131° (1 g/100 mL in MeCN, 589 nm, 20° C.).

¹H NMR (500 MHz, CDCl₃) δ 1.23-1.43 (m, 2H), 1.51 (ddd, 1H), 1.76 (qd,1H), 1.83-1.95 (m, 2H), 2.06-2.16 (m, 2H), 2.92-3.01 (m, 1H), 3.77-3.86(m, 1H), 3.92 (s, 3H), 6.70 (d, 1H), 7.67 (d, 1H), 7.83-7.91 (m, 3H),8.04 (d, 2H), 8.37 (s, 1H).

The second eluted compound was collected and evaporated to give Example18b (13 mg, 38%, 96.0% ee).

Optical rotation: +127° (1 g/100 mL in MeCN, 589 nm, 20° C.).

¹H NMR (500 MHz, CDCl₃) δ 1.22-1.44 (m, 2H), 1.51 (ddd, 1H), 1.76 (qd,1H), 1.92 (d, 2H), 2.02-2.22 (m, 2H), 2.96 (td, 1H), 3.73-3.87 (m, 1H),3.92 (s, 3H), 6.70 (d, 1H), 7.67 (d, 1H), 7.82-7.93 (m, 3H), 8.04 (d,2H), 8.32 (s, 1H)

Example 19:1-Ethyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide

HCl in MeOH (1.2M, 0.3 mL, 0.36 mmol) was added to a solution of1-ethyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]-carbonyl}amino)-1H-pyrazole-5-carboxamide(Intermediate 44, 150 mg, 0.28 mmol) in MeOH (20 mL). The reactionmixture was concentrated in vacuum at 18° C. The residue was dissolvedin MeOH (25 mL) and then concentrated at 16° C. The crude product wasimmediately purified by preparative HPLC on a XBridge C18 column (10 m250×19 ID mm) using a gradient of 5-70% MeCN in a H₂O/MeCN/NH₃(95/5/0.2) buffer system to give the title compound (78 mg, 62%).

¹H NMR (500 MHz, DMSO-d₆) δ 1.12-1.22 (m, 1H), 1.25 (t, 3H), 1.35 (t,1H), 1.42-1.57 (m, 2H), 1.76 (d, 2H), 1.83 (d, 1H), 1.97 (d, 1H), 2.08(d, 1H), 2.75-2.96 (m, 1H), 3.69 (t, 1H), 4.28 (q, 2H), 6.56 (s, 1H),7.38 (s, 2H), 7.89 (d, 2H), 8.00 (d, 2H), 9.48 (s, 1H), 12.74 (s, majorrotamer), 13.09 (minor rotamer) Mixture of rotamers in ratio major:minor1:0.12

MS m/z 449.3 [M+H]⁺

Example 20: N,1-Dimethyl-4-[({(1R,2R and1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide

Step1—4-({[(1R,2R)-2-(4-Bromobenzoyl)cyclohexyl]carbonyl}amino)-N,1-dimethyl-1H-pyrazole-3-carboxamide

T3P (50% in EtOAc, 268 μL, 0.45 mmol) and Et₃N (0.094 mL, 0.67 mmol)were added to a mixture of(1R,2R)-2-(4-Bromobenzoyl)cyclohexanecarboxylic acid (70 mg, 0.22 mmol)and 4-amino-N, 1-dimethyl-1H-pyrazole-3-carboxamide hydrochloride (86mg, 0.45 mmol) in EtOAc (2 mL) and the reaction mixture was heated in amicrowave reactor at 150° C. for 40 min. T3P (50% in EtOAc, 268 μL, 0.45mmol) and Et₃N was added and the reaction mixture was heated in amicrowave reactor at 150° C. for 20 min. The reaction mixture wasdiluted with EtOAc and the organic phase was washed with NaHCO₃ (aq) andbrine. The organic phase was dried using a phase separator andconcentrated to give the subtitle compound (87 mg, crude).

Step2—N,1-Dimethyl-4-[({(1R,2R)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}carbonyl)-amino]-1H-pyrazole-3-carboxamide

A solution of the product from step 1 (86 mg, 0.19 mmol) in DME (1.5 mL)and ethanol (0.5 mL) was added to Pd(dppf)Cl₂*DCM (16 mg, 0.02 mmol) and1H-pyrazol-3-ylboronic acid (21.64 mg, 0.19 mmol) under an atmosphere ofnitrogen. Potassium phosphate (aq, 12M, 0.047 mL, 0.58 mmol) in water(0.5 mL) was added and the reaction mixture was heated in a microwavereactor at 140° C. for 15 min. 1H-pyrazole-3-carboxamide (16 mg, 0.035mmol) and Pd(dppf)Cl₂*DCM (10 mg, 0.012 mmol) was added to the reactionmixture and it was heated in a microwave reactor at 140° C. for 10 min.The reaction mixture was diluted with EtOAc and the organic phase waswashed with water, dried using a phase separator and concentrated invacuum. The crude residue was purified by preparative HPLC on a XBridgeC18 OBD column (5 μm, 19×150 mm ID) using a gradient of 5-95% of MeCN ina H₂O/MeCN/NH₃ (95/5/0.2) buffer system at pH10 as mobile phase to givethe title compound (23 mg, 27%).

¹H NMR (600 MHz, DMSO-d₆) δ 1.20 (q, 1H), 1.43 (t, 1H), 1.52 (q, 2H),1.72-1.88 (m, 2H), 1.97 (d, 1H), 2.04 (d, 1H), 2.77 (d, 3H), 2.84-2.94(m, 1H), 3.74 (t, 1H), 3.80 (s, 3H), 6.86 (s, 1H), 7.85 (s, majorrotamer), 7.91 (s, minor rotamers), 7.97 (d, major rotamer), 8-8.1 (m,3H), 8.28 (d, 1H), 9.80 (s, 1H), 13.09 (s, major rotamer), 13.53 (s,minor rotamer). Mixture of rotamers in ratio major:minor 1:0.21

MS m/z 422.2 [M+H]⁺

Example 21:N,1-Dimethyl-4-[({(1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide

Ice-cooled HCl (2M in dioxane/water, 1:1, 2 mL, 4.00 mmol) was addeddropwise to a solution ofN,1-dimethyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide(Intermediate 47, 0.069 g, 0.13 mmol) in dioxane (3 mL) at 0° C. Thereaction mixture was allowed to reach rt and was then stirred at rt for50 min. The reaction mixture was concentrated in vacuum at 10-15° C. Theresidue was co-evaporated under vacuum at 10-15° C. with dioxane (3×3mL). Methylamine (2 M in THF, 1 mL) was added and the reaction mixturewas evaporated. The crude product was purified by preparative HPLC on aXBridge C18 column (10 μm, 250×19 ID mm) using a gradient of 10-60% MeCNin a H₂O/MeCN/NH₃ (95/5/0.2) buffer system to give the title compound(0.044 g, 75.0%).

¹H NMR (500 MHz, CDCl₃) δ 1.26-1.46 (m, 2H), 1.52 (q, 1H), 1.68-1.79 (m,1H), 1.91 (dd, 2H), 2.12 (t, 2H), 2.36 (s, 3H), 2.72-2.91 (m, 4H),3.7-3.82 (m, 1H), 4.01 (s, 3H), 6.43 (s, 1H), 7.12 (d, 1H), 7.41 (s,1H), 7.83 (d, 2H), 7.88 (s, 1H), 7.98 (d, 2H).

MS m/z 447.3 [M−H]⁻

Example 22:5-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide

HCl (3.8M in water, 145 μL, 0.55 mmol) was added to a solution of5-methyl-4-({[(1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]-carbonyl}amino)-1H-pyrazole-3-carboxamide(Intermediate 48, 190 mg, 0.37 mmol) in a mixture of 1,4-dioxane (3 mL)and water (0.75 mL). The reaction mixture was stirred at rt for 2.5 h.The reaction mixture was diluted with EtOAc and water and the organicphase was washed with NaHCO₃ (sat. aq), brine, dried using a phaseseparator and concentrated in vacuum. The residue was purified bypreparative SFC on a Viridis 2-EP column (5 μm, 30×250 mm ID) usingMeOH/DEA (100:0.5) in CO₂(g) as mobile phase, to give the title compound(94 mg, 59.1%)

¹H NMR (600 MHz, DMSO-d₆) δ 1.14-1.24 (m, 1H), 1.29-1.58 (m, 3H),1.71-2.04 (m, 6H), 2.12-2.33 (m, 4H), 2.78-2.92 (m, 1H), 3.59-3.77 (m,1H), 6.64 (d, 1H), 7.21 (d, 1H), 7.76-8.11 (m, 4H), 9.30 (d, 1H),12.66-13.18 (m, 2H)

Example 23:4-[({(1R,2R)-2-[4-(1H-Pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide

HCl (1.25 M in MeOH, 0.2 mL, 0.25 mmol) was added to a solution of4-({[(1R,2R)-2-{4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide(Intermediate 49, 90 mg, 0.18 mmol) in MeOH (10 mL). The reactionmixture was concentrated in vacuum at 19° C. The residue was dissolvedin MeOH (10 mL) and concentrated in vacuum at 17° C. The residue wasimmediately purified by preparative HPLC on a XBridge C18 column (10 μm250×19 ID mm) using a gradient of 5-80% MeCN in a H₂O/MeCN/NH₃(95/5/0.2) buffer system, to give the title compound (56 mg 75%)

¹H NMR (500 MHz, DMSO) δ 1.11-1.27 (m, 1H), 1.34-1.59 (m, 3H), 1.69-1.84(m, 2H), 1.99 (dd, 2H), 2.78-2.92 (m, 1H), 3.67-3.78 (m, 1H), 6.84 (d,1H), 7.39-8.16 (m, 8H), 9.76 (s, 1H), 13.07 (s, 2H), 13.51 (s, OH).

MS m/z 405.3 [M−H]⁻

Example 24:(1R,2R)—N-(4-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

HCl (3.8M in water, 5 mL, 19 mmol) was added dropwise to a solution of(1R,2R)—N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-{4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxamide(Intermediate 50, 0.46 g, 0.89 mmol) in dioxane (5 mL) cooled in anice-bath and the reaction mixture was stirred while cooling for 1 h. Thereaction mixture was diluted with EtOAc and NaHCO₃ (sat., aq) and theaqueous phase was extracted four times with EtOAc. The combined organicphase was washed with NaHCO₃ (sat., aq), dried using a phase separatorand evaporated in vacuum. The residue was purified by preparative HPLCon a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 15-55%MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system to give the titlecompound (0.298 g, 77%).

¹H NMR (400 MHz, CDCl₃) δ 1.14-1.56 (m), 1.6 (m, 2H), 1.88 (m, 2H), 2.12(t, 2H), 2.95 (m, 1H), 3.69 (m, 3H), 4.30 (t, 2H), 6.70 (d, 1H), 7.65(d, 1H), 7.86 (d, 2H), 8.05 (d, 2H), 8.15 (s, 1H), 8.82 (s, 1H)

Example 25:(1R,2R)—N-[1-Methyl-5-(methylsulfamoyl)-1H-pyrazol-4-yl]-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

HCl (1.25N in MeOH, 0.76 mL) was added to a solution of(1R,2R)—N-[1-methyl-5-(methylsulfamoyl)-1H-pyrazol-4-yl]-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxamide(Intermediate 56, 180 mg, 0.32 mmol) in MeOH (5 mL) at 0° C. and thereaction mixture was stirred at rt for 30 min. The reaction mixture wasconcentrated under vacuum. The residue was purified by preparative HPLCon a XBridge Prep C18 OBD columnd (5 μm, 19×150 mm) using a gradient of17-55% of MeCN in water (NH₄OH, 0.03%) as mobile phase to give the titlecompound (67 mg, 44%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.05-1.29 (1H, m), 1.29-1.60 (3H, m),1.69-1.84 (2H, m), 1.94-2.07 (2H, m), 2.25 (3H, s), 2.87-2.95 (1H, m),3.67-3.74 (1H, m), 3.93 (3H, s), 6.57 (1H, s), 7.80 (1H, s), 7.87-7.90(2H, m), 7.98-8.01 (4H, m), 8.08-8.13 (1H, m), 8.84 (1H, s), 12.75 (1H,bs)

MS m/z 485 [M+H]⁺

Example 26:(1R,2R)—N-(1-Methyl-3-sulfamoyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

1H-Pyrazol-5-ylboronic acid hydrochloride (108 mg, 0.73 mmol), K₂CO₃(353 mg, 2.56 mmol) and Pd(dppf)Cl₂*DCM (104 mg, 0.13 mmol) was added toa solution of(1R,2R)-2-(4-bromobenzoyl)-N-(1-methyl-3-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide(Intermediate 25, 300 mg, 0.64 mmol) in a mixture of dioxane/H₂O (1:1,15 mL) and the reaction mixture was heated at 70° C. for 3 h under anatmosphere of nitrogen. The reaction mixture was extracted with EtOAcand the combined organic layer was washed with water, dried over Na₂SO₄and concentrated under vacuum. The residue was purified by preparativeHPLC on a XBridge Prep C18 OBD column (5 μm, 19×150 mm) using a gradientof 19-55% of MeCN in water (NH₄OH, 0.03%) as mobile phase to give thetitle compound (71 mg, 24%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.10-1.26 (m, 1H), 1.37-1.56 (m, 3H),1.77-1.87 (m, 2H), 1.97-2.09 (m, 2H), 2.89-2.96 (m, 1H), 3.72-3.80 (t,4H), 6.86 (d, 1H), 7.57 (s, 2H), 7.85-8.12 (m, 6H), 13.07 (s, 1H)

MS m/z 457 [M+H]⁺

Example 27:(1R,2R)—N-[5-(Dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

Pd(dppf)Cl₂*DCM (43 mg, 0.06 mmol), K₂CO₃ (108 mg, 0.78 mmol, 3.00equiv) and water (1 mL) was added to a solution of(1R,2R)-2-(4-bromobenzoyl)-N-[5-(dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-yl]cyclohexanecarboxamide(Intermediate 61, 130 mg, 0.26 mmol) and 1H-pyrazol-5-ylboronic acid (59mg, 0.53 mmol) in 1,4-dioxane (10 mL) and the reaction mixture wasstirred at 85° C. for 15 h. The mixture was diluted with EtOAc and theorganic layer was concentrated in vacuum. The residue was purified bypreparative TLC (50% MeOH in DCM) followed by C18 column chromatography(20% MeCN in water) to give the title compound (18.7 mg, 15%) as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ 1.72-1.28 (m, 4H), 1.90 (t, 2H), 2.11 (t, 2H),2.84 (s, 6H), 2.96 (t, 1H), 3.79 (t, 1H), 4.01 (s, 3H), 6.80 (s, 1H),7.72 (s, 1H), 7.99-7.89 (m, 3H), 8.06 (d, 2H)

MS m/z 485 [M+H]⁺

Example 28:(1R,2R)—N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

(1R,2R)-2-(4-Bromobenzoyl)-N-(2-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(Intermediate 67, 330 mg, 0.72 mmol,), Pd(dppf)Cl₂*DCM (117 mg, 0.14mmol), K₂CO₃ (298 mg, 2.16 mmol) and (5-methyl-1H-pyrazol-3-yl)boronicacid (136 mg, 1.08 mmol) were suspended in a mixture of 1,4-dioxane andwater (10:1, 11 mL). The reaction mixture was purged with nitrogen andthen heated at 100° C. for 1 h under an atmosphere of nitrogen. Thereaction mixture was diluted to with EtOAc and water. The solids werefiltered off and the organic layer was washed with water and brine,dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by Flash column chromatography on a C18 column (30 μm, 20 g)using a gradient of 0%→39% of MeCN in a water/NH₄HCO₃ (99.5/0.5) buffersystem as mobile phase, to give the title compound (181 mg, 55%) as awhite solid.

¹H NMR (300 MHz DMSO-d₆) δ 1.19 (m, 1H), 1.48-1.38 (m, 3H), 1.82-1.74(m, 5H), 1.99-1.93 (m, 1H), 2.28-2.16 (m, 4H), 2.90 (t, 1H), 3.51 (s,2H), 3.68 (t, 1H), 4.14-4.10 (t, 2H), 6.55 (s, 1H), 7.89-7.87 (d, 2H),8.04-7.97 (m, 3H), 9.27 (s, 1H), 12.74 (s, 1H)

MS m/z 461 [M+H]⁺

Example 29:(1R,2R)—N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

(1R,2R)-2-(4-Bromobenzoyl)-N-(2-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(Intermediate 67, 300 mg, 0.65 mmol), Pd(dtbpf)Cl₂ (107 mg, 0.13 mmol),K₂CO₃ (271 mg, 1.96 mmol) and (1H-pyrazol-3-yl)boronic acid (110 mg,0.98 mmol) were suspended in a mixture of dioxane and water (6.7:1, 11.5mL). The reaction mixture was purged with nitrogen then heated at 100°C. for 1 h. The reaction mixture was diluted with EtOAc and water andthe solids were filtered off. The organic layer was washed with waterand brine, dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by Flash column chromatography on a C18 column (30 μm, 20g) using a gradient of 0%→37% of MeCN in a water/NH₄HCO₃ (99.5/0.5)buffer system as mobile phase, to give the title compound (1745 mg, 60%)as a white solid.

¹H NMR (300 MHz DMSO-d₆) δ 1.48-1.10 (m, 4H), 1.80-1.70 (m, 2H), 1.80(s, 3H), 2.00-1.93 (m, 1H), 2.19-2.16 (m, 1H), 2.90 (t, 1H), 3.51 (s,2H), 3.70 (t, 1H), 4.14-4.10 (m, 2H), 6.83 (s, 1H), 8.04-7.83 (m, 6H),9.27 (s, 1H), 13.06 (s, 1H)

MS m/z 447 [M+H]⁺

Example 30:(1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide

HCl in MeOH (3 M in MeOH, 5 mL) was added to a solution of(1R,2R)—N-[5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide(Intermediate 68, 520 mg, 1.05 mmol) in MeOH (26 mL) and the reactionmixture was stirred at rt for 1 h. The pH value of the solution wasadjusted to 8 with NaHCO₃ (aq) and the reaction mixture was diluted withEtOAc. The organic phase was washed with water, brine (sat.), dried overNa₂SO₄ and concentrated in vacuum. The residue was purified bypreparative HPLC on a XBridge Prep C18 OBD column (5 μm, 19×150 mm)using a gradient of 37-46% of MeCN in water (0.03% NH₄OH) as mobilephase to give the title compound (80.5 mg, 19%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.32-1.38 (m, 1H), 1.41-1.57 (m, 3H),1.75-1.85 (m, 2H), 1.96-2.05 (m, 2H), 2.91-3.03 (m, 1H), 3.72-3.78 (m,1H), 6.85 (s, 1H), 7.02 (t, J=53.6 Hz, 1H), 7.84-8.04 (m, 6H), 9.71 (s,1H), 13.09 (s, 1H).

MS m/z 414 [M+H]⁺

Example 31: 4-[({(1R,2R and1S,2S)-2-[2-Chloro-4-(1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

Palladium (10% Pd/C moistured by 50% water, 200 mg, 0.09 mmol) and DMSO(40 mg, 0.51 mmol) was added to a solution of 4-[({(1R,6R and1S,6S)-6-[2-chloro-4-(1H-pyrazol-5-yl)benzoyl]cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 74, 50 mg, 0.11 mmol) dissolved in EtOH (20 mL) and thereaction mixture was stirred at rt. Triethylsilane (2 g, 17.20 mmol) wasadded dropwise during 5 min and the reaction mixture was stirred at rtfor 10 min. The reaction mixture was filtered through a syringe filter,the filtrate was concentrated under reduced pressure and the crudeproduct was purified by flash chromatography (0%→33% Aceton in EtOAc).The product containing fractions were collected and concentrated todryness under reduced pressure. The residue was dissolved intert-butanol and freeze-dried to give the title compound (28.0 mg, 56%).

¹H NMR (600 MHz, MeOD) δ 1.29-1.35 (m), 1.42 (t, 2H), 1.5-1.64 (m, 1H),1.88 (d, 2H), 2.01 (d, 1H), 2.15 (d, 1H), 2.8-2.88 (m, 1H), 3.51-3.6 (m,1H), 4.02 (s, 3H), 6.78 (d, 1H), 7.52 (s, 1H), 7.73 (d, 2H), 7.81 (s,1H), 7.91 (s, 1H).

MS m/z 453.2 [M−H]⁻

Example 32: 4-[({(1R,2R and1S,2S)-2-[2-Chloro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

Palladium (10% Pd/C, moistured by 50% water, 200 mg, 0.09 mmol) and DMSO(40 mg, 0.51 mmol) was added to a solution of 4-[({(1R,6R and1S,6S)-6-[2-chloro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 75, 40 mg, 0.09 mmol) in EtOH (20 mL). Triethylsilane (2.5g, 21.5 mmol) was added dropwise at rt during 5 min and the reactionmixture was stirred at rt for 10 min. The reaction mixture was filtered;the filtrate was concentrated in vacuo. The crude product was purifiedby flash chromatography (0%→33% acetone in EtOAc) and the product wasfreeze-dried from tert-butanol to give the title compound (20 mg, 50%).

¹H NMR (600 MHz, MeOD) δ 1.28-1.34 (m), 1.41 (t, 2H), 1.52-1.62 (m, 1H),1.88 (d, 2H), 2.00 (d, 1H), 2.14 (d, 1H), 2.79-2.88 (m, 1H), 3.52-3.59(m, 1H), 4.02 (s, 3H), 6.51 (s, 1H), 7.52 (s, 1H), 7.71 (d, 2H), 7.85(s, 1H).

MS m/z 467.3 [M−H]⁻

Example 33: (1R,2R and1S,2S)—N-(5-Cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

Step 1: (1R,2R and1S,2R)-2-(4-Bromobenzoyl)-N-(5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)cyclohexanecarboxamide

T3P (50% in EtOAc, 383 μL, 0.64 mmol) was added to a mixture of (1R,2Rand 1S,2S)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (100 mg, 0.32mmol), 5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-amine (89 mg, 0.64mmol), and Et₃N (134 μL, 0.96 mmol) and the reaction mixture was heatedin a microwave reactor at 150° C. for 30 min. The reaction mixture wasdiluted with EtOAc and the organic phase was extracted twice with NaHCO₃(sat., aq) and brine. The organic phase was dried using a phaseseparator and concentrated in vacuo to give the crude subtitle compound(148 mg).

MS m/z 433.1 [M+2]⁺

Step 2: (1R,2R and1S,2S)—N-(5-Cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

1H-Pyrazol-5-ylboronic acid (35.8 mg, 0.32 mmol), and Pd(dppf)Cl₂*DCM(25.9 mg, 0.03 mmol) were added to a mixture of (1R,2R and1S,2R)-2-(4-bromobenzoyl)-N-(5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)cyclohexanecarboxamide(Example 33 Step 1, 138 mg, 0.32 mmol) in DME (2.4 mL) and water (0.8mL). A solution of K₃PO₄ (204 mg, 0.96 mmol) in water (0.90 mL) wasadded to the reaction mixture and it was heated in a microwave reactorat 140° C. for 15 min. The reaction mixture was diluted with EtOAc andthe organic phase was extracted with water, dried using a phaseseparator and concentrated in vacuo. The crude product was purified bypreparative HPLC on a Xbridge C18 column (5 μm, 150×19 ID mm) using agradient of 5-95% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2, pH 10) buffer systemas mobile phase to give the title compound (45 mg, 33%).

¹H NMR (600 MHz, DMSO) δ 0.56 (tt, 2H), 0.67-0.79 (m, 2H), 1.13-1.24 (m,1H), 1.37 (t, 1H), 1.45-1.58 (m, 2H), 1.61 (tt, 1H), 1.78 (d, 1H), 1.87(d, 1H), 1.96 (d, 1H), 2.17 (d, 1H), 2.88-2.96 (m, 1H), 3.74 (t, 1H),3.92 (s, 3H), 6.84 (d, 1H), 7.84 (s, 1H), 7.96 (d, majorrotamer),7.97-8.97 (m, minor rotamer), 8.03 (d, 2H), 9.70 (s, 1H), 13.08(s, major rotamer), 13.5 (s, minor rotamer). Mixture of rotamers inratio major:minor 1:0.19.

Example 34: 4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

Palladium (10% Pd/C, 25 mg, 0.02 mmol) was added to a solution of4-[({(1R,6R or1S,6S)-6-[2-fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohex-3-en-1-yl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide(Intermediate 82, 52 mg, 0.12 mmol) in MeOH (5 mL) and the reactionmixture was stirred under an atmosphere of hydrogen (1 atm) at rt for 1h. The reaction mixture was filtered through a pad of celite and thefiltrate was concentrated in vacuo. The crude product was purified bypreparative HPLC on a XBridge C18 column (10 μm, 250×19 ID mm) using agradient of 20-65% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system asmobile phase to give the title compound (13 mg, 25%).

¹H NMR (400 MHz, CDCl₃) δ 1.17 (tt, 1H), 1.24-1.39 (m, 1H), 1.39-1.56(m, 1H), 1.68 (tt, 1H), 1.86 (t, 2H), 2.03-2.19 (m, 2H), 2.81 (t, 1H),3.56-3.69 (m, 1H), 4.04 (s, 3H), 6.61 (d, 1H), 6.92 (s, 2H), 7.47 (d,1H), 7.52-7.64 (m, 3H), 7.78 (t, 1H), 8.22 (s, 1H).

MS m/z 437.2 [M−H]⁻

Example 35: 4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide

HCl (1.25 M in MeOH, 0.5 mL, 0.63 mmol) was added to a solution4-({[(1R,2R or 1S,2S)-2-{2-fluoro-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]-carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxamide(Intermediate 85, 270 mg, 0.52 mmol) in MeOH (10 mL) and the reactionmixture was concentrated in vacuo at 16° C. The residue was dissolved inMeOH (10 mL) and concentrated in vacuo at 16° C. The crude product waspurified by preparative HPLC on a XBridge C18 column (10 μm, 250×19 IDmm) using a gradient of 5-80% MeCN in a H₂O/ACN/NH₃ (95/5/0.2) buffersystem as mobile phase to give the title compound (120 mg, 53%).

¹H NMR (500 MHz, MeOD) δ 1.18-1.33 (m, 1H), 1.37-1.52 (m, 2H), 1.52-1.64(m, 1H), 1.88 (d, 2H), 2.04-2.17 (m, 2H), 2.8-2.94 (m, 1H), 3.53-3.65(m, 1H), 3.81 (s, 3H), 6.78 (d, 1H), 7.5-7.79 (m, 3H), 7.84 (t, 1H),7.98 (s, 1H).

MS m/z 437.3 [M−H]⁻

Example 36: 4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide

HCl (1.25 M in MeOH, 0.5 mL, 0.63 mmol) was added to a solution of4-({[(1R,2R or 1S,2S)-2-{2-fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1-methyl-1H-pyrazole-3-carboxamide(Intermediate 86, 216 mg, 0.40 mmol) in MeOH (10 mL) and the reactionmixture was concentrated in vacuo at 16° C. The residue was dissolved inMeOH (10 mL) and concentrated in vacuo at 16° C. The crude product waspurified by preparative HPLC on a XBridge C18 column (10 μm, 250×19 IDmm) using a gradient of 5-80% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffersystem as mobile phase to give the title compound (126 mg, 69%).

¹H NMR (500 MHz, MeOD) δ 1.19-1.33 (m, 1H), 1.45 (q, 2H), 1.52-1.62 (m,1H), 1.88 (d, 2H), 2.05-2.17 (m, 2H), 2.33 (s, 3H), 2.86 (ddd, 1H),3.54-3.65 (m, 1H), 3.82 (s, 3H), 6.52 (s, 1H), 7.58 (dd, 2H), 7.82 (t,1H), 7.98 (s, 1H).

Example 37: 4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide

The enantiomers of the trans-racemate 4-[({(1R,2R and1S,2S)-2-[2-fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide(intermediate 92, 44 mg, 0.10 mmol) were separated by chiral SFCchromatography on a Chiralpak IC HPLC column (5 μm, 250×20 ID mm). 23 mg(16 mg/mL in EtOH) was injected and eluted with 35% EtOH/DEA (100/0.5)in CO₂ (175 bar) at a flow rate of 70 mL/min and detected at 260 nm. Thesecond eluted compound was collected and freeze-dried from a mixture ofMeCN/H₂O (1:1). The residue was dissolved in EtOAc and washed with KHSO₄(0.01M, aq). The aqueous phase was extracted with EtOAc and the combinedorganic phase was dried using a phase separator and concentrated invacuo to give the title compound (0.019 g, 99.7% ee).

Optical rotation: +73° (0.5 g/100 mL in MeCN, 589 nm, 20° C.).

¹H NMR (500 MHz, MeOD) δ 1.31-1.68 (m, 4H), 1.91 (s, 2H), 2.15 (s, 2H),2.34 (s, 3H), 2.89 (d, 1H), 3.60 (t, 1H), 4.01 (s, 3H), 6.54 (s, 1H),7.41-7.76 (m, 3H), 7.87 (t, 1H).

HRMS m/z 453.2079 [M+H]⁺

Example 38: 4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide

HCl (1.2M in MeOH) (0.1 mL, 0.12 mmol) was added to a solution of4-({[(1R,2R or 1S,2S)-2-{2-fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1H-pyrazole-5-carboxamide(Intermediate 94, 24 mg, 0.05 mmol) in MeOH (10 mL) and the reactionmixture was concentrated in vacuo at 17° C. The residue was dissolved inMeOH (10 mL) and concentrated in vacuo at 17° C. The crude product waspurified by preparative HPLC on a XBridge C18 column (10 μm, 250×19 IDmm) using a gradient of 5-70% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffersystem as mobile phase to give the title compound (10 mg, 46%).

¹H NMR (500 MHz, DMSO) δ 1.17 (q, 1H), 1.41 (dd, 3H), 1.79 (d, 2H), 2.01(d, 2H), 2.27 (s, 3H), 2.73-2.91 (m, 1H), 3.42-3.55 (m, 1H), 6.62 (s,1H), 7.48 (s, 1H), 7.57-7.78 (m, 3H), 7.84 (t, 1H), 8.03 (s, 1H), 9.76(s, 1H), 12.96 (d, 2H).

Example 39: (1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide

(3-Methyl-1H-pyrazol-5-yl)boronic acid (164 mg, 1.30 mmol), K₂CO₃ (180mg, 1.29 mmol) and Pd(dppf)Cl₂*DCM (106 mg, 0.13 mmol) was added to asolution of (1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(Intermediate 95, 300 mg, 0.65 mmol) in a mixture of dioxane and water(10:1, 15 mL) and the reaction mixture was stirred at 100° C. for 2 h.The reaction mixture was filtered and the filtrate was concentrated invacuo. The residue was diluted with DCM and the organic layer was washedthree times with water. The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified by preparative HPLC on a XBridge Shield RP 18 OBD Column (5 um,150×19 ID mm) using a gradient of 45-95% MeOH in a NH₄HCO₃/H₂O (10 mM)buffer system as mobile phase to give the title compound (90 mg, 30%).

¹H NMR (400 MHz, DMSO-d₆): δ 1.27-1.05 (m, 1H), 1.52-1.29 (m, 3H), 1.78(s, 2H), 2.10-1.98 (t, 2H), 2.28 (s, 3H), 2.95 (t, 1H), 3.50 (t, 1H),3.60 (s, 2H), 4.32 (t, 2H), 6.62 (s, 1H), 7.32-6.95 (m, 1H), 7.80-7.68(m, 2H), 7.98-7.81 (m, 2H), 8.32 (s, 1H), 9.16 (s, 1H).

MS m/z 465 [M+H]⁺

Example 40: 4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1,2,5-oxadiazole-3-carboxamide

Step 1: 4-({[(1R,2R or1S,2S)-2-{2-Fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-1,2,5-oxadiazole-3-carboxamide

A solution of K₂CO₃ (110 mg, 0.80 mmol) in water (2 mL) was added to asolution of3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 139 mg, 0.48 mmol) and 4-({[(1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexyl]carbonyl}amino)-1,2,5-oxadiazole-3-carboxamide(Intermediate 96, 87 mg, 0.20 mmol) in 1,4-dioxane (3 mL) and thereaction mixture was purged with N₂(g). Pd(dtbpf)Cl₂ (15 mg, 0.02 mmol)was added to the reaction mixture and it was heated in a microwavereactor at 90° C. for 1 h. The reaction mixture was allowed to cool andused directly in the next step.

Step 2: 4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1,2,5-oxadiazole-3-carboxamide

HCl (2M, aq, 2 mL) was added to the crude reaction mixture of4-({[(1R,2R or1S,2S)-2-{2-fluoro-4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}-cyclohexyl]carbonyl}amino)-1,2,5-oxadiazole-3-carboxamide(Example 40 Step 1 above) and the reaction mixture was stirred at rt for1 h. The reaction mixture was concentrated in vacuo and the water phasewas extracted with DCM. The organic phase was dried using a phaseseparator and concentrated in vacuo. The crude compound was purified bypreparative HPLC on a Xbridge C18 column (5 μm, 150×19 ID mm) using agradient of 5-95% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system asmobil phase to give the title compound (1.4 mg, 2%).

MS m/z 441.17 [M+H]⁺

Example 41: 3-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-5-methyl-1,2-oxazole-4-carboxamide

Step 1: 3-({[(1R,2R or1S,2S)-2-(4-Bromo-2-fluorobenzoyl)cyclohexyl]carbonyl}amino)-5-methyl-1,2-oxazole-4-carboxylicacid

(1R,2R or 1S,2S)-2-(4-Bromo-2-fluorobenzoyl)cyclohexanecarbonyl fluoride(Intermediate 97, 107 mg, 0.32 mmol) dissolved in DCM (1 mL) was addedto a refluxing solution of 3-amino-5-methylisoxazole-4-carboxylic acid(50 mg, 0.36 mmol) and quinoline (0.046 mL, 0.39 mmol) in DCM (1 mL) andthe reaction mixture was stirred at reflux for 2 days. The reactionmixture was diluted with tert-butyl methyl ether, and the pH of thereaction mixture was adjusted to 12-14 using NaOH (1M, aq). The organiclayer was washed with brine, NH₄Cl (aq) and brine, dried using aphase-separator and concentrated in vacuo. DCM was added to the residueand the mixture was concentrated in vacuo to give the subtitle compound(107 mg).

Step 2: 3-({[(1R,2R or1S,2S)-2-(4-Bromo-2-fluorobenzoyl)cyclohexyl]carbonyl}amino)-5-methyl-1,2-oxazole-4-carboxamide

DIPEA (124 μL, 0.71 mmol) and TBTU (114 mg, 0.35 mmol) were added to asolution of crude 3-({[(1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexyl]carbonyl}amino)-5-methyl-1,2-oxazole-4-carboxylicacid (Example 41 Step 1, 107 mg) in DMF (3 mL) and the reaction mixturewas stirred for 5 min. NH₄Cl (30 mg, 0.57 mmol) was added and thereaction mixture was stirred at rt for 2 h. The reaction mixture wasdiluted with EtOAc and the organic phase was washed with NaHCO₃ (sat.,aq), brine, NH₄Cl (sat., aq), and brine, dried using a phase separatorand concentrated in vacuo to give the subtitle compound (96 mg).

Step 3: 3-({[(1R,2R or1S,2S)-2-{2-Fluoro-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-5-methyl-1,2-oxazole-4-carboxamide

A solution of K₂CO₃ (117 mg, 0.85 mmol) in degassed water (1 mL) wasadded to a degassed solution of 3-({[(1R,2R or1S,2S)-2-(4-bromo-2-fluorobenzoyl)cyclohexyl]-carbonyl}amino)-5-methyl-1,2-oxazole-4-carboxamide(Example 41 Step 2, 96 mg) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(83 mg, 0.30 mmol) in dioxane (1 mL). The solution was evacuated andpurged with nitrogen (g). Pd(dtbpf)Cl₂ (3 mg, 4 μmol) was added and thereaction mixture was heated at 60° C. for 2 h. The reaction mixture wascooled to rt and used directly in the next step.

Step 4: 3-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-5-methyl-1,2-oxazole-4-carboxamide

A solution of HCl (4M in dioxane, 2.5 mL, 10.0 mmol) in water (2.5 mL)was added dropwise to the reaction mixture of 3-({[(1R,2R or 1S,2S)-2-{2-fluoro-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexyl]carbonyl}amino)-5-methyl-1,2-oxazole-4-carboxamide(Example 41 Step 3 above) and it was stirred at rt for 10 min. Thereaction mixture was diluted with EtOAc and the organic phase was washedtwice with NaHCO₃ (sat., aq). The combined aqueous phase was extractedwith EtOAc. The combined organic layer was dried using a phase separatorand concentrated in vacuo. The crude product was purified by preparativeHPLC on a XBridge C18 column (10 μm, 250×19 ID mm) using a gradient of5-45% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system as mobile phase.The compound containing fractions were collected, evaporated andpartitioned between EtOAc and water. The organic phase was dried using aphase separator and concentrated in vacuo to give the title compound(1.5 mg, 1%).

MS m/z 440.2 [M+H]⁺

Example 42: 1-Ethyl-4-[({(1R,2R and1S,2S)-2-[4-(1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide

A solution of K₂CO₃ (147 mg, 1.06 mmol) in degassed water (1.5 mL) wasadded to a mixture of 4-({[(1R,2R and 1S,2S)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1-ethyl-1H-pyrazole-3-carboxamide(Intermediate 98, 119 mg, 0.27 mmol), 1H-pyrazol-5-ylboronic acid (45mg, 0.40 mmol) and Pd(dppf)Cl₂*DCM (22 mg, 0.03 mmol) in degasseddioxane (1.5 mL), and the reaction mixture was heated in a microwavereactor at 100° C. for 1 h. The reaction mixture was partitioned betweenEtOAc and NaCl (sat., aq) and the aqueous phase was extracted twice withEtOAc. The combined organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by preparativeHPLC on a Xbridge Prep C18 column (5 μm, 150×19 ID mm) using a gradientof 5-95% MeCN in a H₂O/MeCN/NH₃ (95/5/0.2) buffer system as mobil phaseto give the title compound (39 mg, 34%).

¹H NMR (600 MHz, DMSO) δ 1.13-1.25 (m, 1H), 1.31 (t, 3H), 1.43 (t, 1H),1.51 (t, 2H), 1.79 (dd, 2H), 2.00 (dd, 2H), 2.82-2.91 (m, 1H), 3.73 (t,1H), 4.08 (q, 2H), 6.85 (d, 1H), 7.48 (s, 1H), 7.63 (s, 1H), 7.79-8.11(m, 6H), 9.77 (s, 1H), 13.09 (s, 1H).

MS m/z 433.2 [M−H]⁻

Example 43:(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1,3,4-oxadiazol-2-yl)cyclohexanecarboxamide

Step 1:(1R,2R)-2-(4-Bromobenzoyl)-N-(1,3,4-oxadiazol-2-yl)cyclohexanecarboxamide

LiOH (213 mg, 8.89 mmol) was added to a solution of ethyl5-({[(1R,2R)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-1,3,4-oxadiazole-2-carboxylate(Intermediate 99, 1 g, 2.22 mmol) in MeOH (15 mL) and water (15 mL) andthe reaction mixture was stirred at rt for 1 h. The reaction mixture wasconcentrated in vacuo. The residue was dissolved in water (50 mL) andthe pH of the solution was adjusted to 1-2 using HCl (1M, aq). Theaqueous phase was extracted three times with DCM. The combined organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo to givethe subtitle compound (1 g).

MS m/z 378 [M+H]⁺

Step 2:(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1,3,4-oxadiazol-2-yl)cyclohexanecarboxamide

(3-Methyl-1H-pyrazol-5-yl)boronic acid (666 mg, 5.29 mmol), K₂CO₃ (730mg, 5.28 mmol), Pd(dppf)Cl₂*DCM (432 mg, 0.53 mmol) and water (1 mL)were added to a solution of(1R,2R)-2-(4-bromobenzoyl)-N-(1,3,4-oxadiazol-2-yl)cyclohexanecarboxamide(Example 43 Step 1, 1 g, 2.64 mmol) in dioxane (10 mL) and the reactionmixture was heated at 80° C. for 4 h under an atmosphere of nitrogen.The reaction mixture was diluted with EtOAc and washed twice with waterand the combined aqueous phase was extracted with EtOAc. The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by preparative HPLC on a XBridge ShieldC18 OBD Column (5 um, 150×19 ID mm) using a gradient of 5-85% of MeCN ina H₂O/HCO₂H (100/0.1) buffer system as mobile phase to give the titlecompound (84 mg, 8%) as a light yellow solid.

¹H NMR (300 MHz, DMSO): δ 1.03-1.57 (m, 4H), 1.69-1.87 (m, 2H),1.90-2.13 (m, 2H), 2.28 (s, 3H), 2.96 (s, 1H), 3.72 (t, 1H), 6.57 (s,1H), 7.90 (d, 2H), 8.02 (d, 2H), 8.92 (s, 1H), 11.79 (s, 1H), 12.76 (s,1H).

MS m/z 380 [M+H]⁺

Example 44: (1R,2R and1S,2S)—N-(3-Methyl-1,2-oxazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

Step 1: (1R,2R and 1S,2S)-2-(4-Bromobenzoyl)-N-(3-methyl-1,2-oxazol-5-yl)cyclohexanecarboxamide

T3P (50% inEtOAc, 383 μL, 0.64 mmol) was added to a mixture of (1R,2Rand 1S,2S)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (100 mg, 0.32mmol), 3-methyl-1,2-oxazol-5-amine (63.1 mg, 0.64 mmol), and Et₃N (134μL, 0.96 mmol) in EtOAc (3 mL) and the reaction mixture was heated in amicrowave reactor at 150° C. for 30 min. The reaction mixture wasdiluted with EtOAc and the organic phase was washed twice with NaHCO₃(sat., aq) and brine, dried using a phase separator and concentrated invacuo to give the subtitle compound (95 mg, 76%).

MS m/z 391.2 [M−H]⁻

Step 2: (1R,2R and1S,2S)—N-(3-Methyl-1,2-oxazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

A solution of K₃PO₄ (155 mg, 0.73 mmol) in water (0.6 mL) was added to amixture of (1R,2R and1S,2S)-2-(4-bromobenzoyl)-N-(3-methyl-1,2-oxazol-5-yl)cyclohexanecarboxamide(Example 44 Step 1, 95 mg, 0.24 mmol), 1H-pyrazol-5-ylboronic acid (27mg, 0.24 mmol) and Pd(dppf)Cl₂*DCM (20 mg, 0.02 mmol) in a mixture ofDME (1.8 mL) and EtOH (0.6 mL) and the reaction mixture was heated at140° C. for 15 min. 1H-Pyrazol-5-ylboronic acid (27 mg, 0.24 mmol) andPd(dppf)Cl₂*DCM (20 mg, 0.02 mmol) were added and the reaction mixturewas heated at 140° C. for 15 min. The reaction mixture was diluted withEtOAc and the organic layer was washed with water, dried using a phaseseparator and concentrated in vacuo. The crude product was purified bypreparative HPLC on a XBridge C18 OBD column (5 μm, 150×19 ID mm) usinga gradient of 10-60% MeCN in a H₂O/NH₃ (100/0.2, pH10) buffer system asmobile phase and then by preparative HPLC on a Sunfire Prep C18 column(5 μm, 150×19 ID mm) using a gradient of 5-95% MeCN in a HCO₂H/H₂O(0.1M) buffer system as mobile phase to give the title compound (10 mg,11%).

¹H NMR (600 MHz, DMSO) δ 1.11-1.21 (m, 1H), 1.32 (d, 1H), 1.39-1.5 (m,1H), 1.55 (d, 1H), 1.77 (d, 1H), 1.85 (d, 1H), 2.01 (d, 1H), 2.11 (s,4H), 2.82-2.97 (m, 1H), 3.66-3.85 (m, 1H), 5.97 (s, 1H), 6.86 (d, 1H),8.04 (d, 5H), 11.64 (s, 1H), 13.10 (s, 1H).

MS m/z 379.2 [M+H]⁺

Example 45: (1R,2R and1S,2S)—N-(4-Methyl-1,3-oxazol-2-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

Step 1: (1R,2R and1S,2S)-2-(4-Bromobenzoyl)-N-(4-methyl-1,3-oxazol-2-yl)cyclohexanecarboxamide

DIPEA (336 μL, 1.93 mmol), and TBTU (371 mg, 1.16 mmol) was added to astirred solution of (1R,2R and1S,2S)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (300 mg, 0.96 mmol)and 4-methyl-1,3-oxazol-2-amine (113 mg, 1.16 mmol) in DCM (5 mL) andthe reaction mixture was stirred at rt for 3 days. The reaction mixturewas washed with Na₂CO₃ (1M, aq) and the phases were separated. Theorganic layer was dried using a phase separator and concentrated invacuo. The crude product was purified by flash chromatography (40% EtOAcin heptane) to give the subtitle compound (85 mg, 23%).

Step 2: (1R,2R and1S,2S)—N-(4-Methyl-1,3-oxazol-2-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

K₂CO₃ (113 mg, 0.82 mmol) dissolved in water (1 mL) was added to amixture of (1R,2R and1S,2S)-2-(4-bromobenzoyl)-N-(4-methyl-1,3-oxazol-2-yl)cyclohexanecarboxamide(Example 45 Step 1, 80 mg, 0.20 mmol), 1H-pyrazol-5-ylboronic acid (46mg, 0.41 mmol) and Pd(dppf)Cl₂*DCM (13.2 mg, 0.02 mmol) in dioxane (2mL). The reaction mixture was evacuated and purged with nitrogen (g),and then heated at 80° C. for 2.5 h. The reaction mixture waspartitioned between EtOAc and NaHCO₃ (sat., aq). The organic phase wasfiltered using a phase separator, concentrated in vacuo, and the crudeproduct was purified by flash chromatography (80% EtOAc in heptane). Theproduct containing fractions were collected, evaporated and trituratedwith Et₂O. The crude product was purified by flash chromatography (80%EtOAc in heptane) and the product containing fractions were combined andevaporated to dryness and finally triturated with Et₂O to give the titlecompound (21 mg, 28%).

¹H NMR (500 MHz, CDCl₃, 28° C.) δ 1.15-1.38 (m, 2H), 1.38-1.57 (m, 1H),1.77-1.94 (m, 3H), 2.07 (d, 5H), 2.92 (d, 1H), 3.69-3.87 (m, 1H), 6.69(d, 1H), 7.09 (s, 1H), 7.65 (d, 1H), 7.86 (d, 2H), 8.02 (d, 2H).

MS m/z 377.2 [M−H]⁻

Example 46: (1R,2R and1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

Step 1: (1R,2R and1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxamide

Pd(dtbpf)Cl₂ (6.97 mg, 10.84 μmol) and a solution of K₂CO₃ (150 mg, 1.08mmol) in water (1.5 mL) were added to a mixture of (1R,2R and1S,2S)-2-(4-bromobenzoyl)-N-(5-cyano-1-methyl-1H-pyrazol-4-yl)cyclohexanecarboxamide(Intermediate 43, 150 mg, 0.36 mmol) and3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 3, 106 mg, 0.36 mmol) in dioxane (2 mL) and the reactionmixture was evacuated and purged with nitrogen (g) three times, and thenheated at 80° C. for 1 h. The reaction mixture was diluted with EtOAcand the organic phase was washed twice with NaCl (sat., aq). Thecombined aqueous phase was extracted twice with EtOAc. The combinedorganic layer was dried using a phase separator and concentrated invacuo to give the subtitle compound (180 mg).

MS m/z 499.3 [M−H]⁻

Step 2: (1R,2R and1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

A solution of HCl (4M in dioxane, 0.5 mL) in water (0.5 mL) was added toa solution of (1R,2R and1S,2S)—N-(5-cyano-1-methyl-1H-pyrazol-4-yl)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxamide(Example 45 Step 1, 180 mg) in dioxane (2 mL) and the reaction mixturewas stirred at rt for 15 min. The reaction mixture was concentrated andthe crude product was purified by preparative HPLC on a Waters SunfireC18 OBD column (5 μm, 150×19 ID mm) using a gradient of 5-95% MeCN in aHCO₂H/H₂O (0.1M, pH3) buffer system and then by preparative HPLC on aXBridge C18 column (10 μm, 250×19 ID mm) using a gradient of 20-60% MeCNin a H₂O/MeCN/NH₃ (95/5/0.2) buffer system as mobile phase to give thetitle compound (28 mg, 19%).

¹H NMR (500 MHz, DMSO) δ 1.09-1.23 (m, 1H), 1.33 (t, 1H), 1.4-1.57 (m,2H), 1.76 (d, 1H), 1.84 (d, 1H), 1.98 (d, 1H), 2.05 (d, 1H), 2.27 (s,3H), 2.86-2.94 (m, 1H), 3.69-3.78 (m, 1H), 3.89 (s, 3H), 6.56 (s, 1H),7.70 (s, 1H), 7.88 (d, 2H), 8.00 (d, 2H), 10.51 (s, 1H), 12.7 (s, 1H).

MS m/z 417.1 [M+H]⁺

Example 47: (1R,2R and1S,2S)—N-(3-Cyclopropyl-1,2,4-thiadiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

Step 1: (1R,2R and1S,2S)-2-(4-Bromobenzoyl)-N-(3-cyclopropyl-1,2,4-thiadiazol-5-yl)cyclohexanecarboxamide

T3P (50% in EtOAc, 383 μL, 0.64 mmol) was added to a mixture of (1R,2Rand 1S,2S)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (100 mg, 0.32mmol), 3-cyclopropyl-1,2,4-thiadiazol-5-amine (91 mg, 0.64 mmol), andEt₃N (134 μL, 0.96 mmol) in EtOAc (3 mL) and the reaction mixture washeated in a microwave reactor at 150° C. for 30 min. The reactionmixture was diluted with EtOAc and the organic phase was extracted withNaHCO₃ (sat., aq) and brine, dried using a phase separator andconcentrated in vacuo to give the subtitle compound (151 mg).

MS m/z 434.2 [M+H]⁺

Step 2: (1R,2R and1S,2S)—N-(3-Cyclopropyl-1,2,4-thiadiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

A solution of K₃PO₄ (204 mg, 0.96 mmol) in water (0.9 mL) was added to amixture (1R,2R and1S,2S)-2-(4-bromobenzoyl)-N-(3-cyclopropyl-1,2,4-thiadiazol-5-yl)cyclohexanecarboxamide(Example 47 Step 1, 139 mg, 0.32 mmol), 1H-pyrazol-5-ylboronic acid (36mg, 0.32 mmol), and Pd(dppf)Cl₂*DCM (26 mg, 0.03 mmol) in a mixture ofDME (2.4 mL) and EtOH (0.8 mL) and the reaction mixture was heated at140° C. for 15 min. The reaction mixture was diluted with EtOAc and theorganic phase was washed with water, dried using a phase separator andconcentrated in vacuo. The crude product was purified by preparativeHPLC on a Xbridge Prep OBD C18 column (5 μm, 150×19 ID mm) using agradient of 5-95% MeCN in a H₂O/NH₃ (100/0.2, pH10) buffer system asmobile phase to give the title compound (35 mg, 26%).

¹H NMR (600 MHz, DMSO) δ 0.85-1.05 (m, 4H), 1.09-1.24 (m, 1H), 1.32 (d,1H), 1.39-1.51 (m, 1H), 1.81 (dd, 2H), 1.96-2.21 (m, 3H), 2.95-3.09 (m,1H), 3.72-3.87 (m, 1H), 6.86 (d, 1H), 7.85 (s, 1H), 7.89-8.14 (m, 4H),13.10 (s, 2H).

MS m/z 422.2 [M+H]⁺

Example 48: (1R,2R and1S,2S)—N-(3-Methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

A solution of K₃PO₄ (38 mg, 0.18 mmol) in water (0.2 mL) was added to amixture of (1R,2R and1S,2S)-2-(4-bromobenzoyl)-N-(3-methyl-1,2-thiazol-5-yl)cyclohexanecarboxamide(Intermediate 100, 24 mg, 0.06 mmol), 1H-pyrazol-5-ylboronic acid (7 mg,0.06 mmol), and Pd(dppf)Cl₂ (5 mg, 5.89 μmol) in a mixture of DME (0.6mL) and EtOH (0.2 mL) and the reaction mixture was heated at 140° C. for15 min. The reaction mixture was diluted with EtOAc and the organicphase was extracted with water, dried using a phase separator andconcentrated in vacuo. The crude product was purified by preparativeHPLC on a Xbridge Prep C18 OBD column (5 μm, 150×19 ID mm) using agradient of 5-95% MeCN in a H₂O/NH₃ (100/0.2, pH10) buffer system asmobile phase to give the title compound (8 mg, 35%).

¹H NMR (600 MHz, DMSO) δ 1.1-1.3 (m, 1H), 1.3-1.44 (m, 1H), 1.44-1.64(m, 2H), 1.78 (d, 1H), 1.86 (d, 1H), 1.97-2.12 (m, 2H), 2.29 (s, 3H),2.84-3.04 (m, 1H), 3.81 (s, 1H), 6.69 (s, 1H), 6.86 (d, 1H), 7.73-8.15(m, 5H), 11.96 (s, 1H), 13.10 (s, 1H).

MS m/z 395.2 [M+H]⁺

Example 49: (1R,2R and1S,1S)—N-(4-Cyano-3-methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide

A solution of K₃PO₄ (74 mg, 0.35 mmol) in water (0.3 mL) was added to amixture of (1R,2R and1S,1S)-2-(4-bromobenzoyl)-N-(4-cyano-3-methyl-1,2-thiazol-5-yl)cyclohexanecarboxamide(Intermediate 101, 51 mg, 0.12 mmol), 1H-pyrazol-5-ylboronic acid (13mg, 0.12 mmol), and Pd(dppf)Cl₂*DCM (10 mg, 0.01 mmol) in a mixture ofDME (1 mL) and EtOH (0.3 mL) and the reaction mixture was heated at 140°C. for 15 min. The reaction mixture was diluted with EtOAc and theorganic phase was washed with water, dried using a phase separator andconcentrated in vacuo. The crude product was purified by preparativeHPLC on a Xbridge Prep C18 OBD column (5 μm, 150×19 ID mm) using agradient of 5-95% MeCN in a H₂O/NH₃ (100/0.2, pH10) buffer system asmobile phase to give the title compound (14 mg, 29%).

¹H NMR (600 MHz, DMSO) δ 1.15-1.24 (m, 1H), 1.28-1.39 (m, 1H), 1.46 (d,1H), 1.59 (d, 1H), 1.78 (s, 1H), 1.87 (d, 1H), 2.05 (s, 1H), 2.12 (d,1H), 2.41 (s, 3H), 3.21 (s, 1H), 3.84 (s, 1H), 6.86 (d, 1H), 7.76-8.2(m, 5H), 12.83 (s, 1H), 13.10 (s, 1H).

MS m/z 420.1 [M+]⁺

1. A compound according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, C₁-C₃alkyl, halo, C₁-C₃ alkoxy, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy; each ofR² and R³ is independently H, C₁-C₃ alkyl, C₁-C₃ alkoxy, —CN or halo; R⁴is H, —CH₃, —CH₂F, —CHF₂, —CF₃ or halo; Ring A contains 2 double bonds;each X₁, X₂, X₃ and X₄ of Ring A is independently CR⁵, CH, O, S, NR⁶ orN; wherein at least one of X₁, X₂, X₃ and X₄ in Ring A is NR⁶; each R⁵is optionally and independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃ haloalkoxy, —S(O)_(p)R⁷, —CN, —CONR′R″, or C₃-C₆cycloalkyl; each p is independently 0, 1 or 2; R⁶ is H, —CH₃ or —CH₂CH₃;or wherein when X₄ is CR⁵ and X₃ is NR⁶, then the R⁵ and R⁶ may be takentogether to form a 5 to 6-membered heterocyclyl ring fused to Ring A,which heterocyclyl may optionally contain an additional heteroatomselected from N, O and S; said fused heterocyclyl may additionallycontain a carbonyl or a —S(O)₂ directly adjacent to a heteroatomtherein; and may be further substituted with one or two substituentsselected from the group consisting of —CH₃ and halo; R⁷ is —CH₃ or—NR′R″; and each R′ and R″ is independently —H or —CH₃; provided thatthe total number of substituents on Ring A is 0, 1 or 2; and furtherprovided that when R⁵ and R⁶ are not combined to form a heterocyclylring fused to Ring A, that the total number of R⁵ and R⁶ substituentswhich is alkyl and/or haloalkyl is 0 or
 1. 2. The compound of claim 1,wherein R⁴ is —H or —CH₃.
 3. The compound of claim 1, wherein R² and R³are each independently —F or —H.
 4. The compound of claim 1, wherein R¹is —H.
 5. The compound of claim 1, according to formula (II):

or a pharmaceutically acceptable salt thereof, wherein each X₁, X₂ andX₄ of Ring A is independently CR⁵, CH, or N; wherein at least one of X₁,X₂ and X₄ in Ring A is N; and X₃ is O, S or NR⁶; or wherein when X₄ isCR⁵ and X₃ is NR⁶, then the R⁵ and R⁶ may be taken together to form a 5to 6-membered heterocyclyl ring fused to Ring A, which heterocyclyl mayoptionally contain an additional heteroatom selected from N, O and S;said fused heterocyclyl may additionally contain a carbonyl or a —S(O)₂directly adjacent to a heteroatom therein; and may be furthersubstituted with one or two substituents selected from the groupconsisting of —CH₃ and halo; and R¹, R², R⁴, R⁵ and R⁶ are as defined inclaim
 1. 6. The compound of claim 1, wherein X¹ is CH or CR⁵, wherein R⁵is as defined in claim
 1. 7. The compound of any claim 1, wherein X⁴ isCR⁵ wherein R⁵ is as defined in claim
 1. 8. The compound of any claim 1,wherein Ring A is an optionally and independently substituted pyrazole,triazole, oxazole, thiazole, oxadiazole or thiadiazole.
 9. The compoundof claim 1, according to formula (III):

or a pharmaceutically acceptable salt thereof; wherein: X¹ is CH or CR⁵;X² is N; X³ is O, S, or NR⁶; X⁴ is CH or CR⁵; R² is —H or —F; R⁵ is—S(O)₂NR′R″, —SO₂CH₃; —C(O)NR′R″, —CN, C₁-C₂ alkoxy, C₁-C₂ haloalkoxy orC₁-C₂ haloalkyl; R⁶ is H, —CH₃ or —CH₂CH₃; each R′ and R″ isindependently —H or —CH₃; or wherein when X₄ is CR⁵ and X₃ is NR⁶, thenthe R⁵ and R⁶ may be taken together to form a 5 to 6-memberedheterocyclyl ring fused to Ring A, which heterocyclyl may optionallycontain an additional heteroatom selected from N, O and S; said fusedheterocyclyl may additionally contain a carbonyl or a —S(O)₂ directlyadjacent to a heteroatom therein; and may be further substituted withone or two substituents selected from the group consisting of —CH₃ andhalo; and R⁴ is as defined in claim
 1. 10. The compound of claim 9,wherein one of X¹ is CH, X² is N and X³ is NR⁶ and R⁶ is as defined inclaim
 9. 11. The compound of claim 9, wherein X⁴ is CR⁵ and X³ is NR⁶and together the R⁵ and R⁶ substituents form a 5-6 membered heterocyclylring fused to Ring A, to form a bicyclic ring together with ring Aselected from:


12. The compound of claim 1, according to formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CH or CR⁵;R⁵, if present, is —CH₃; R² is —H or —F; R⁴ is —H or —CH₃; and R⁸ is —Hor CH₃.
 13. A compound of claim 1, according to the formula (V):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CH or CR⁵;R² is —H or —F; R⁴ is —H or —CH₃; R⁵, if present, is —CH₃; and R⁶ is —Hor —CH₃; provided that R⁵ and R⁶ are not both —CH₃ at the same time. 14.The compound of claim 1, according to formula (VI):

or a pharmaceutically acceptable salt, wherein: X¹ is CH or CR⁵; R² is—H or —F; R⁴ is —H or —CH₃; R⁵, if present, is —CH₃; and R⁶ is —H or—CH₃; provided that R⁵ and R⁶ are not both —CH₃ at the same time. 15.The compound of claim 1, according to formula (VII):

or a pharmaceutically acceptable salt, wherein: one of X¹ and X⁴ is CH,and the other is CR⁵; R² is —H or —F; R⁴ is —H or —CH₃; R⁵ is —CH₃ orC₁-haloalkyl; and R⁶ is —H or —CH₃; provided that the total number of R⁵and R⁶ substituents in the A ring which is alkyl is 0 or
 1. 16. Acompound selected from the group consisting of: Trans(+) or Trans(−)1-Methyl-4-[({(1R,2R or1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;1-Methyl-4-[({(1R,2R)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;Trans(−) (1S,2S or1R,2R)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;Trans(+) (1R,2R or1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1H-pyrazol-4-yl)cyclohexanecarboxamide;(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide;((1R,2R)—N-[1-Methyl-5-(methylsulfonyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-[3-(Difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]-2-(4-(1H-pyrazol-5-yl)benzoyl)-cyclohexanecarboxamide;(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-3-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide;(1R,2R)—N-(2,3-Dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;Trans(−) (1R,2R or1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide;Trans (+/−) (1R,2R and1S,2S)—N-(5-Methoxy-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;Trans(−) (1R,2R or1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;Trans(+) (1S,2S or1R,2R)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;1-Ethyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-5-carboxamide;Trans (±)-N,1-Dimethyl-4-[({(1R,2R and1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide;N,1-Dimethyl-4-[({(1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;5-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;4-[({(1R,2R)-2-[4-(1H-Pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;(1R,2R)—N-(4-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-[1-Methyl-5-(methylsulfamoyl)-1H-pyrazol-4-yl]-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-(1-Methyl-3-sulfamoyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-[5-(Dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;(1R,2R)—N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;and(1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;Trans(±)-4-[({(1R,2R and1S,2S)-2-[2-Chloro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;Trans(±)-4-[({(1R,2R and1S,2S)-2-[2-Chloro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;Trans(+)-(1R,2R and1S,2S)—N-(5-Cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide;4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide;4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-5-carboxamide;(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide;4-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1,2,5-oxadiazole-3-carboxamide;3-[({(1R,2R or1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)-amino]-5-methyl-1,2-oxazole-4-carboxamide;Trans(±)-1-Ethyl-4-[({(1R,2R and1S,2S)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide;(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1,3,4-oxadiazol-2-yl)cyclohexanecarboxamide;Trans(+)-(1R,2R and1S,2S)—N-(3-Methyl-1,2-oxazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;Trans(+)-(1R,2R and1S,2S)—N-(4-Methyl-1,3-oxazol-2-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;Trans(+)-(1R,2R and1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;Trans(+)-(1R,2R and1S,2S)—N-(3-Cyclopropyl-1,2,4-thiadiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;Trans(+)-(1R,2R and1S,2S)—N-(3-Methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;and Trans(+)-(1R,2R and1S,1S)—N-(4-Cyano-3-methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;or a pharmaceutically acceptable salt thereof.
 17. A compound accordingto claim 16, which is(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide;or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, as claimed in claim 1, and at least onepharmaceutically acceptable carrier, diluent, or excipient. 19-20.(canceled)
 21. A method of treating diseases or conditions in whichinhibition of FLAP is beneficial, comprising administering to a patientin need thereof an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, as claimed in claim 1.